Research On The Synthesis Of Ticagrelor

Ticagrelor as a small molecule selective anticoagulant,has obvious inhibitory effect on ADP induced platelet aggregation.It can effectively alleviate the symptoms of patients with acuting coronary heart disease.It is the first reversible type combined with oral P2Y12 adenosine diphosphate receptor antagonists.Ticagrelor was developed by AstraZeneca pharmaceutical company,and was respectively approved by the European Medicines Agency(EMEA)and USA food and Drug Administration(FDA)in 2010 and 2011.It was listed in the EU and American,and the brand name is Brilinta.A new synthetic route for Ticagrelor was presented in this thesis.It had advantages over those previously reported routes,such as using cheap raw materials,simple operation process and suitable for large scale production.The synthesis route started from 4,6-dichloro-5-nitro-2-(propylsulfanyl)pyrimidine,via a route of reduction,nucleophilic substitution,cyclization and deprotection to obtain the Ticagrelor.There is two highlights of this route."One-pot" process was applied successfully to simplify seven steps operation before to only four steps.Crystallization process for the final product was optimized.Type II crystal products,which is same with the original research varieties,was obtained.The verification results showed that the quality of three consecutive batch products were agree with the certification of USP.The content were all over 99.7%.The total yield reached 55%.The new synthesis route had already applied in workshop for production of Ticagrelor.For the structure characterization of the samples,the data is basically identical with literature.At the same time,the product of the physical and chemical indexes were tested,to formulate the quality standard.To inspect the quality of three batch of amplification products stability data,the experimental results show that product quality is stable,and the content of the related substances is same with the control sample.