Synthesis Of The Intermediate TG-1.2 Of Ticagrelor And Optimization Of Preparation Process Technique

With the aging of population is increasing, the incidence of cardiovascular disease is becoming more and more high. As the top of mortality, cardiovascular disease has caused extensive concern of the world. Many countries and some international drug groups are looking and developing a new kind of anticoagulants. Ticagrelor is a new type of small molecule anticoagulants that is developed by Astra Zeneca company. It is a broad-spectrum, efficient and new kind of adenosine diphosphate receptor antagonist which is aalso the first kind in the world that has reversible effect. It has has aroused widespread attention at home and abroad. At present, AstraZeneca company has applied for patent of the world, the United States and China. Its midbody and part of its technology patents will expire in 2018. Because ticagrelor’s patent is about to expire, and because of its good drug effect and wide prospect of market, it has a huge development value.This article first made an systematic analysis on the pharmaceutical development trend, summarized the research status of anticoagulants, and made a detailed evaluation on the pharmacology, pharmacokinetics, patent situation market prospects and synthetic route of ticagrelor. From the synthetic route, we can see that the synthesis of ticagrelor is mainly depending on the synthesis midbody TG-1.2, while the midbody TG-1.2 has 4 chiral carbon atoms and these 4 chiral carbon atom will directly affect the pharmacological activity of ticagrelor. On the basis of comprehensive literature, this paper has conducted primary exploration on the synthetic route of midbody TG- 1.2 and finally developed a technology process route that is simple, of low production cost, environmentally friendly. This paper took cyclohexanone oxime as the starting material, and after 12 reactions including chlorine nucleophilic addition, Diels Alder reaction, benzyl chloroformate amino protection, double bond oxidation, double hydroxyl protection, benzyl chloroformate protection, chiral resolution, benzyl chloroformate amino protection, Williamson aethrization reaction, carbonyl reduction reaction, benzyl chloroformate deprotection, salt forming reaction, the target product--ticagrelor midbody TG-1.2 was got, with the overall yield 9.1% and the purity of product 99.7%. After structural identification by 1H NMR and MS, all the midbody, impurities and products were proved to be correct and the after rotation determination, according with the requirements. First, this paper made detailed research on the mechanism of impurities in each step and got the generated reason of impurities. Then it selectively studied on the inventory of raw materials, reaction temperature, feed rate, catalyst, reaction solvents, solvent crystallization, water and catalyst replacement, optimized the reaction of each step and determined the best technology process. Secondly, on the basis of the literature, this paper adopted continuous cascade reaction on compound TG-1 to compound TG-3 and made the yield of compound TG-3 reach 87%, increasing 33% compared to the literature. Finally, during the carbonyl reduction reaction from compound TG-10 to compound TG-11, this paper adopted the mixture of sodium borohydride and solid acid catalyst to replace lithium aluminium hydride, which is more expensive and more dangerous, and made the yield reach 82%. This route has not been reported in literature, so it has certain degree of novelty. By making improvement and optimization on every reaction of ticagrelor midbody TG-1.2, it not only improved the yield but also decreased the cost. Besides, it laid a good foundation for preparing ticagrelor by green and environmental friendly industrialization.