Fluoridation method

Abstract

A method for the fluoridation of an iodonium salt with a fluoride ion source which can be carried out in an aqueous reaction solvent.

1 . A method of making an aromatic fluorine-labelled compound of formula (III):
   Q-F  (III)
   wherein:   Q is phenyl or phenyl substituted with one or more C 1-10  alkyl, —O(C 1-10  alkyl), —C(═O)C 1-10  alkyl, —C(═O)NR 6 (C 1-10  alkyl), —(C 1 -C 6  alkyl), C 5-14  aryl, —O(C 5-14  aryl), —C(═O)C 5-14  aryl, —C(═O) NR 6 (C 5-14  aryl, C 5-14  heteroaryl, —O(C 5-14  heteroaryl), —C(═O)C 5-14  heteroaryl, —C(═O)NR 6 (C 5-14  heteroaryl), C 3-10  cycloalkyl, —O(C 3-10  cycloalkyl), —C(═O)(C 3-10  cycloalkyl), —C(═O)NR 6 (C 3-10  cycloalkyl), C 3-10  heterocyclyl, —O(C 3-10  heterocyclyl), —C(═O)(C 3-10  heterocyclyl), —C(═O)NR 6 (C 5-14  heterocyclyl),
 wherein R 6  is H, C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, C 3 -C 10  heterocyclyl, C 4 -C 10  aryl or C 4 -C 10  heteroaryl; 
   any of which may optionally be substituted with OH, NHR 6 , COOH or protected versions any of these groups; or alternatively   any two adjacent substituents may form a four- to six-membered carbocyclic or heterocyclic ring, optionally fused to a further aromatic, heteroaromatic, carbocyclic or heterocyclic ring;   comprising:   reacting fluoride, from a fluoride source, with a compound of the formula (I) or (II) in a solvent which is either 100% water or a mixture of water and a water-miscible solvent   
       
         
           
           
               
               
           
         
         wherein 0 is as defined above; 
         each of R 1 -R 5  is independently hydrogen, —O(C 1-10  alkyl) or C 1-10  alkyl; and 
         Y −  is trifluoromethane sulfonate (triflate), perfluoro C 2 -C 10  alkyl sulphonate, trifluoroacetate, methane sulfonate (mesylate) toluene sulfonate (tosylate) or tetraphenylborate. 
       
     
     
         2 . A method as claimed in  claim 1 , wherein the reaction solvent is 100% water. 
     
     
         3 . A method as claimed in  claim 1  wherein the reaction solvent is a mixture of water and a water miscible solvent. 
     
     
         4 . A method as claimed in  claim 3 , wherein the water miscible solvent is acetonitrile, ethanol, methanol, tetrahydrofuran or dimethylformamide. 
     
     
         5 . A method as claimed in  claim 3  wherein the volume:volume ratio of water:water-miscible solvent is between 1:99 and 1:1. 
     
     
         6 . A method as claimed in  claim 5  wherein the volume:volume ratio of water:water-miscible solvent is from 10:90 to 30:70. 
     
     
         7 . A method as claimed in  claim 1 , wherein the fluoride ion source is potassium fluoride, cesium fluoride or sodium fluoride. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . A method as claimed in  claim 1  wherein, in the compound of Formula II, the solid support is polystyrene, polyacrylamide, polypropylene or glass or silicon coated with such a polymer. 
     
     
         11 . A method as claimed in  claim 1  wherein the solid support is in the form of discrete particles or is a coating on the inner surface of a reaction vessel. 
     
     
         12 . A method as claimed in  claim 1 , wherein, in the compound of Formula II the linker is C 1-20  alkyl or C 1-20  alkoxy, attached to the solid support via an amide, ether or a sulphonamide bond or the linker is a polyethylene glycol (PEG) linker. 
     
     
         13 . (canceled) 
     
     
         14 . A method as claimed in  claim 1 , wherein the aromatic moiety Q has an additional substituent selected from OH, NHR 6  or halogen. 
     
     
         15 . A method of making a compound of formula (III)
   Q-F  (III)
   wherein the group Q is:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         comprising: 
         reacting fluoride, from a fluoride source, with a compound of the formula (I) or (II) in a solvent which is either 100% water or a mixture of water and a water-miscible solvent 
       
       
         
           
           
               
               
           
         
         wherein Q is as defined above; 
         each of R 1 -R 5  is independently hydrogen, —O(C 1-10  alkyl) or C 1-10  alkyl; and 
         Y −  is trifluoromethane sulfonate (triflate), perfluoro C 2 -C 10  alkyl sulphonate, trifluoroacetate, methane sulfonate (mesylate) toluene sulfonate (tosylate) or tetraphenylborate. 
       
     
     
         16 . A method as claimed in one of  claims 1  or  15 , wherein the fluorine in the compound of formula (III) is  18 F  − . 
     
     
         17 . A method as claimed in  claim 16 , wherein the compound of the formula (III) is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . A method as claimed in  claim 1 , further comprising, in any order, one or more of the following steps:
 (i) removal of excess  18 F − , for example by ion-exchange chromatography; and/or   (ii) removal of the protecting groups; and/or   (iii) removal of organic solvent; and/or   (iv) formulation of the resultant compound as an aqueous solution.   
     
     
         19 . A kit for the production of an aromatic fluorine-labelled compound of formula (III) of  claim 1 , the kit comprising:
 (i) a vial containing an aqueous solvent for dissolving the fluoride ion source; and   (ii) a reaction vessel containing an iodonium salt of formula (I) or (II).   
     
     
         20 . A kit as claimed in  claim 19 , wherein the solvent is 100% water. 
     
     
         21 . A kit as claimed in  claim 19  wherein the solvent is a mixture of water and a water miscible solvent. 
     
     
         22 . A kit as claimed in  claim 21 , wherein the water miscible solvent is acetonitrile, ethanol, methanol, tetrahydrofuran or dimethylformamide. 
     
     
         23 . A kit as claimed in  claim 21  wherein the volume:volume ratio of water:water-miscible solvent is between 1:99 and 1:1. 
     
     
         24 . A kit as claimed in  claim 23  wherein the volume:volume ratio of water:water-miscible solvent is from 10:90 to 30:70. 
     
     
         25 . (canceled) 
     
     
         26 . A kit as claimed in  claim 19  wherein the iodonium salt is a compound of general formula (II) and the solid support comprises a coating on the surface of the reaction vessel. 
     
     
         27 . A kit as claimed in  claim 19 , wherein the reaction vessel is a cartridge or a microfabricated vessel. 
     
     
         28 . A kit as claimed in  claim 19 , further comprising a vessel comprising a source of fluoride ions.