Improved Synthesis Research Of Alogliptin Benzoate

The dissertation mainly studied the improvement on the synthesis of DPP-4 inhibitor Alogliptin benzoate.The dissertation includes two chapters as following.The first chapter introduced the research progress of antidiabetic agents and Alogliptin benzoate briefly,also outline the synthetic methods of Alogliptin benzoate and analysis the advantages and disadvantages of these methods.The second chapter studied the synthesis improvement of Alogliptin benzoate.Alogliptin benzoate was synthesized from 6-chloro-3-methyl pyrimidine-2,4(1H,3H)-dione and 2-(bromomethyl)benzonitrile by nucleophilic substitution to give 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile(5)with yield of 93.6%.Then we used(R)-tert-butyl piperidin-3-ylcarbamate to react with 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)be nzonitrile(5)to give(R)-tert-butyl(1-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)piperidin-3-yl)carbamate(10).The compound 10 did not need to be isolated and purified from reaction liquid,and p-toluenesulfonic acid was added into the reaction liquid to eliminate protecting group Boc to give Alogliptin.Under the optimal conditions,the total yield of the two step could reach 83.2%.Then we studied the preparation of Alogliptin benzoate by salification with yield of 92.6%.We investigated the teaction conditions such as solvent,alkali,teaction temperature,feeding way,materials proportion and so on.We merges the reaction of giving compound 10 and the reaction of giving Alogliptin.After completion of these improvments,the route has three steps with an overall yield of 72.1%.Compared to the traditional craft,the improved process is 13% higher in yield,lower in by-product and cost,easier to operate,and more suitable for industrial production.