Study On The Synthesis Of The Trelagliptin Succinate And Related Substances

Diabetes mellitus typeⅡis a long term metabolic disorder that is characterized by high blood sugar,insulin resistance,and relative lack of insulin.Common symptoms include increased thirst,frequent urination,and unexplained weight loss.Symptoms may also include increased hunger,feeling tired,and sores that do not heal.Often symptoms come on slowly.Long-term complications from high blood sugar include heart disease,strokes,diabetic retinopathy which can result in blindness,kidney failure,and poor blood flow in the limbs which may lead to amputations.The sudden onset of hyperosmolar hyperglycemic state may occur;however,ketoacidosis is uncommon.TypeⅡdiabetes is primarily due to obesity and not enough exercise in people who are genetically predisposed.It makes up about 90%of cases of diabetes,with the other 10%due primarily to diabetes mellitus type 1 and gestational diabetes.In diabetes mellitus type 1 there is an absolute lack of insulin due to breakdown of islet cells in the pancreas.Diagnosis of diabetes is by blood tests such as fasting plasma glucose,oral glucose tolerance test,or A1C.There are many types of typeⅡdiabetes drugs,according to the effect of the action can be divided into:the promotion of insulin synthesis and secretion of drugs,drugs to improve insulin sensitivity,α-glucosidase inhibitor class of drugs,insulin analogues and pancreas amyloid peptide analogues and other five major categories of drugs.Currently on the market is the best prospect DPP-IV inhibitors,are promoting insulin synthesis and secretion of drugs,the main drawback of such drugs is of short duration,administered frequently.Trelagliptin succinate,(R)-2-((6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-pyrimidin-1(2H)-yl)methyl)-4-fluoro-benzonitrile succinate,is developed by Takeda Pharmaceutical Company.It is a novel DPP-IV inhibitors.It is expected to become the first can be administered once weekly small molecule diabetes drugs.March 26,2015 approved for marketing in Japan for long-term treatment of typeⅡdiabetes medication once a week,and can effectively improve the condition of patients.It is convenient to use so can improves the patient’s compliance,otherwise,it has less adverse reactions.So it is a novel,potential drug for typeⅡdiabetes.Objectives:The aim is to establish the synthesis methods of Trelagliptin succinate,to optimize the synthetic technologies and to establish the analysis methods.Methods:Synthetic route of Trelagliptin succinate is settled by accessing to relevant literature and experiment design.Methyl urea and diethyl malonate as the starting material by cyclization of 3-methyl-6-chloro-uracil(5)and then by chlorinated and brominated compounds product 6-step nucleophilic reactions(8)occurs 8 and then by the pro-nuclear reaction and then with succinic acid salt in Trelagliptin succinate(1).The structure of intermediates and target products were confirmed by melting point,mass specrum and nuclear magnetic.High performance liquid chromatography(HPLC)method was used for the chemical and optical purity determination of the target.Results:Under the process we designed,Trelagliptin succinate and related substances were synthesized successfully and were confirmed by MS-ESI(m/z)and ~1H-NMR.The chemical and optical purity of Trelagliptin determinated by HPLC method.Moreover,some of the synthetic technologies were optimized.Trelagliptin succinate:white solid,mp.195.5~196.5℃.Conclusions:In this paper,using methyl urea and diethyl malonate as the starting material,the target product trelagliptin succinate and related substances were obtained by 6 steps.Some of the synthethetic technologies were optimized.The operations of the process were simple,and the generation cycle was short,and the reaction conditions were mild.Synthesized and related substances R-1,R-2 and R-3,the structure was confirmed.