Study On The Method For Synthesis Of Ticagrelor Drug Intermediate

This thesis aims to optimize the synthesis process of Ticagrelor intermediate and develop the new synthetic methods for the synthesis of chiral cyclopropylamine.This thesis mainly consists of two parts as follows:In the first part,we reviewed the properties,the pharmacological effects,and the relative advantages in anti-coagulation treatment of Ticagrelor.As well the typical synthetic methods for synthsis of ticagrelor intermediate cyclopropylamine 7.Secondly,we have designed and developed the synthetic route to prepare the ticagrelor intermediate cyclopropylamine 7.The key step was through Wittig-Homer-Wadsworth cyclopropanation to construct cyclopropane ring.Furthermore,the reaction mechanism of Wittig-Homer-Wadsworth cyclopropanation was suggested.We have investigated the effects of various alkali reagents,the amounts of base and phosphoryl triethylorthoacetate,the reaction temperatures,solvents on the yields of reaction.In addition,the asymmetric reduction of compound 3 was furnished by CBS-reduction,which provided the chance to preparation of chiral cyclopropylamine 7In the second part,a new synthetic method for the ticagrelor intermediate cyclopropylamine 7 was carried out.Condensation of 3,4-difluorobenzaldehyde with nitromethane provided the nitrolefin 9.The Corey-Chaykovsky cyclopropanation of nitrolefin 9 with sulfur ylide reagents was studied.Unfortunately,it is failed to construct the three-membered ring skeleton.The method for the synthesis of ticagrelor intermediate cyclopropylamine 7 has been developed.This synthetic route has some advantages such as cheap and readily available raw materials,simple operation,high yield good stereoselctivity,which is feasible to a large-scale preparation.