Study On The Deoxyfluorination Of Alcohols And Applications

In the design of the molecular structure of drugs,due to the special physical and chemical properties of the fluorine atom,it has shown great advantages in the modification of the drug structures.1)Strong electronegativity,the covalent bond polarized between carbon atom and fluorine atom has a powerful coulomb attraction,enabling the carbon-fluorine bond exist stably.2)Bioisostere,fluorine atom is often used as an bioisostere of hydrogen atom,and with little effect on the structure and pharmacological activities of drugs.Therefore,the construction of C-F bonds can significantly improve the stability of metabolism,lipid solubility and membrane permeability for prodrugs.Due to the abundant source of alcohol-containing organic compounds,deoxyfluorination reaction based on aliphatic hydroxyl groups is one of the most direct and effective methods to form aliphatic carbon-fluorine bonds.In the process of deoxyfluorination,aliphatic alcohols are activated by deoxyfluorination reagents through initially converting hydroxyl groups to leaving groups,and nucleophilic fluorine sources emerged subsequently react in a pathway of bimolecular nucleophilicto construct C-F bonds successfully.The reported deoxyfluorination reagents have deficiencies on stability and reaction efficiency,and also difficult to achieve radiolabeling process through the direct use of potassium fluoride.All of those deficiencies has limited the construction of C-F bonds in drugs.In this background,we have developed a method for the deoxyfluorination that potassium fluoride is available directly in the deoxyfluorination of alcohols.The main process is that potassium fluoride reacts quickly with N-Phenyl-bis?trifluoromethanesulfonimide?,producing the actived gas intermediate called trifluoromethylsulfonyl fluoride,and undergoes dehydroxyfluorination in situ with alcohols under the catalysis of base.The reaction conditions are simple and rapid,and fluorination of various compounds such as primary alcohols,secondary alcohols,heterocyclic alcohols,sterols,amino acids,small molecule polypeptides,and commercially available drug molecules has been achieved in the substrate expansion.In addition,this method was applied to the ¹⁸F radiolabeling process.The ¹⁸F labeling of 2,3,4,6-Tetra-O-benzyl-D-glucopyranose was initially achieved by manual labeling,and the radiochemical conversion was 45.9%,the radiochemical yield was 35.7%.