Study On Synthesis Process Of Ticagrelor

With the changes of lifestyle,more and more middle-aged person and elderly are suffering from the threat of cardiovascular disease.According to the third china resident sample survey of cause of death,cardiovascular disease has become the first cause of death.Therefore,the research of the pathology and treatment of cardiovascular diseases is challenging and realistic significance.Arterial thrombosis is a major factor in the formation of thrombotic cardiovascular disease,and platelets play a key role in the process of arterial thrombosis.Hence studying antiplatelet drugs is the main point for the treatment of cardiovascular disease.There are many targets on the platelet membrane for the drugs,such as cyclooxygenase(COX-1),thromboxane A2(TXA2),adenosine diphosphate(ADP)receptor,GPⅡb / Ⅲa receptor,and the ADP receptor is a popular target for antiplatelet drugs research.Ticagrelor(ticagrelor / brilinta)is developed by Astra Zeneca,it is orally,direct-acting,reversible P2Y12 adenosine diphosphate receptor antagonist,July 23,2011,the FDA approved it used to reduce the incidence of acute coronary syndrome(ACS)in patients with thrombotic cardiovascular.The administration of import agents have been approved by SFDA,and the patents of ticagrelor in China is about to expire,so the research of ticagrelor has broad market prospects.The author have consulted a large number of patents and literature for choosing synthetic routes of ticagrelor and optimizing its synthesis process,then determined the route for the synthesis is: with diethyl malonate and thiourea as the starting material via cyclization reaction,substitution reaction,nitration reaction,chlorination reaction,reduction reaction,and then got 2-propylthio-4,6-dichloro-5-aminopyrimidine;and then with 2-[[(3a R,4S,6R,6a S)-6-amino-tetrahydro-2,2-dimethyl-4Hcyclopenta-1,3-dioxolan-4-yl] oxy] ethanol monochloro-substituted,a triazole ring,and(1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine of mandelates single chlorine substitution,and finally got ticagrelor by the hydrolysis(a total yield of 20.9% in thiourea).The final product structure ticagrelor confirmed by high resolution mass spectrometry and nuclear magnetic resonance.Compared with the literature,the synthesis process has improved the operation,it is simple,less cost and the higher total yield and purity,so it is more suitable for industrial production.