Method for preparation of organofluoro compounds in alcohol solvents

Abstract

The present invention relates to a method for preparation of organofluoro compounds containing radioactive isotope fluorine-18. More particularly, the present invention relates to a method for preparation of organofluoro compound [ 18 F]florbetaben or [ 18 F]AV-45 having <Chemistry Formula 11> and <Chemistry Formula 12>, respectively, by reacting fluorine salt containing radioactive isotope fluorine-18 with alkyl halide or alkyl sulfonate in the presence of alcohol of Chemistry Formula 1 as a solvent to obtain high yield of organofluoro compound. Synthesis reaction according to the present invention may be carried out under mild condition to give high yield of the organofluoro compounds and the reaction time is decreased, and thereby is suitable for the mass production of the organofluoro compounds.

1 . A method for preparation of an organofluoro compound containing fluorine-18 by reacting fluorine salt containing fluorine-18 with alkyl halide or alkyl sulfonate in the presence of alcohol of Chemistry Formula 1 as solvent, wherein the organofluro compound is [ 18 F]florbetaben or [ 18 F]AV-45 having <Chemistry Formula 11> and <Chemistry Formula 12>, respectively. <Chemistry Formula 1> 
     
       
         
         
             
             
         
       
     
     (wherein R 1 , R 2  and R 3  are hydrogen or C 1 ˜C 18  alkyl group) 
     
       
         
         
             
             
         
       
     
   
   
       2 . The method of  claim 1 , wherein R 1  is hydrogen or C 1 ˜C 18  alkyl group; R 2  is hydrogen or C 1 ˜C 18  alkyl group; and R 3  is hydrogen or C 1 ˜C 18  alkyl group. 
   
   
       3 . The method of  claim 1 , wherein R 1  is methyl or ethyl; R 2  is methyl or ethyl; and R 3  is methyl or ethyl. 
   
   
       4 . The method of  claim 1 , wherein the alcohol of the Chemistry Formula 1 is selected from the group consisting of primary alcohols of methanol, ethanol, n-propanol, n-butanol, amyl alcohol, n-hexyl alcohol, n-heptanol, and n-octanol; secondary alcohols of isopropanol, isobutanol, isoamyl alcohol, and 3-pentanol; and tertiary alcohols of t-butanol, t-amyl alcohol, 2,3-dimethyl-2-butanol, 2-(trifluoromethyl)-2-propanol, 3-methyl-3-pentanol, 3-ethyl-3-pentanol, 2-methyl-2-pentanol, 2,3-dimethyl-3-pentanol, 2,4-dimethyl-2-pentanol, 2-methyl-2-hexanol, 2-cyclopropyl-2-propanol, 2-cyclopropyl-2-butanol, 2-cyclopropyl-3-methyl-2-butanol, 1-methylcyclopentanol, 1-ethylcyclopentanol, 1-propylcyclopentanol, 1-methylcyclohexanol, 1-ethylcyclohexanol and 1-methylcycloheptanol. 
   
   
       5 . The method of  claim 1 , wherein the alcohol of Chemistry Formula 1 is selected from the group consisting of t-butanol, t-amyl alcohol, 2,3-dimethyl-2-butanol and 2-(trifluoromethyl)-2-propanol. 
   
   
       6 . The method of  claim 1 , wherein the fluorine salt is cesiumfluoride or tetraalkylammonium fluoride, and the alcohol is selected from the group consisting of t-butanol, t-amyl alcohol, 2,3-dimethyl-2-butanol and 2-(trifluoromethyl)-2-propanol. 
   
   
       7 . The method of  claim 1 , wherein the fluorine salt is alkali metal fluorides, alkaline earth metal fluorides or ammonium fluoride,
 wherein,   the alkali metal is selected from the group consisting of lithium, sodium, potassium, rubidium, and cesium; and   the alkaline earth metal is selected from the group consisting of magnesium, calcium, strontium, and barium.   
   
   
       8 . The method of  claim 7 , wherein the ammonium fluoride is selected from the group consisting of quaternary ammonium fluorides including tetrabutylammonium fluoride and benzyltrimethylammonium fluoride, tertiary ammonium fluorides including triethylammonium fluoride and tributylammonium fluoride, secondary ammonium fluorides including dibutylammonium fluoride and dihexylammonium fluoride, and primary ammonium fluorides including butylammonium fluoride and hexylammonium fluoride. 
   
   
       9 . The method of  claim 1 , wherein the fluorine salt is cesium fluoride or tetraalkylammonium fluoride. 
   
   
       10 . The method of  claim 9 , wherein the cesium fluoride or the tetraalkylammonium fluoride is adsorbed on a support selected from the group consisting of Celite, Molecular Sieve, alumina, and silica gel. 
   
   
       11 . The method of  claim 1 , wherein the amount of the fluorine salt is 1.0˜10 equivalents for the alkyl halide or alkyl sulfonate containing [ 18 F]fluoride; wherein 1 pg˜100 ng of the [ 18 F]fluoride is used for 1 mg of the alkyl halide or alkyl sulfonate.