Study On The Synthesis Of Falecalcitriol Fluorinated Intermediate

Falecalcitriol is an analog of calcitriol in which a fluorine atom replaces thehydrogen on calcitriol carbons 26 and 27.Falecalcitriol is similar in structure to calcitriol,but the pharmacokinetics of falecalcitriol is different from that of calcitriol.The fluorine atom at the end of the side chain has been shown to impede the catabolism of the molecule.falecalcitriol is only partially metabolized in the human body,and this intermediate retains considerable biological activity.Fluorine also affects binding to vitamin D-binding proteins.Chlortriol has a slightly lower affinity for vitamin D-binding protein and clears faster than calcitriol.Despite the short circulating half-life of falecalcitriol,its affinity with vitamin D receptors is reduced by3 times compared to calcitriol,which can effectively prevent the occurrence of hypercalcemia and hypercholesterolemia.falecalcitriol is metabolized slowly in target tissues,so that the biological activity of falecalcitriol in the body is prolonged and effective,so falecalcitriol is better for the treatment of secondary hyperparathyroidism.At present,the domestic research on chemical synthesis of fluorotriol is still regarded as a technical blank.Therefore,it is of great significance for the research on the synthesis technology of falecalcitriol in the current medical and clinical fields in China.The research team has carefully designed and proposed a new technologyroute for the synthesis of fluoropyritol from two fragments:on the one hand,vitamin D₂ is used as a raw material synthesis of vitamin D derivative intermediate A,on the other hand with 4,4,4-trifluoro-3-hydroxy-3-Trifluoromethyl-butyric acid is used as the raw material through carboxylic acid reduction,iodination reaction,and triphenylphosphine to synthesize fragment B,TBSCl hydroxyl protection synthesis fragment C,and finally intermediate A and fluorine-containing intermediate fragment C After splicing,the final product of fluorocalciferol is synthesized by reduction and light inversion and deprotection.This thesis mainly synthesizes the fluorinated intermediate ylide phosphonium salt and simulates the splicing of the fluorinated intermediate ylide phosphonium salt with benzaldehyde.At the same time,it explores the reaction factors of each step in the synthesis of fluorinated fragments and simulated splicing to find the best reaction conditions.