Method for Monofluoromethylation of Organic Substrates to Prepare Biologically Active Organic Compounds

Abstract

Described is a process for the preparation of monofluoromethylated organic biologically active compounds using monofluoromethylated reagents. Fluticasone Propionate and Fluticasone Furoate can be prepared using, for example, S-monofluoromethyl-S-phenyl- 2,3,4,5 -tetramethylphenylsulfonium tetrafluoroborate as monofluoromethylating reagent instead of bromofluoromethane.

What is claimed is: 
     
         1 . A method of preparing a pharmaceutically active compound containing a “CH 2 F” moiety on a sulphur atom, which method comprises the use of a monofluoromethylating reagent characterized by one of the following formulas II and III: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1 , R 2 , R 3  is independently selected from the group consisting of hydrogen, alkyl or aryl; and 
         R 4  is an anion suitable to form a salt of the reagents presented above, selected from the group consisting of tetrafluoroborate, triflate and halogen. 
       
     
     
         2 . A method according to  claim 1 , wherein the monofluoromethylating reagent is a compound with Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1 , R 2  and R 3  is independently selected from the group consisting of hydrogen, alkyl or aryl; and 
         R 4  is selected from the group consisting of tetrafluoroborate, triflate and halogen. 
       
     
     
         3 . A method according to  claim 1 , wherein the monofluoromethylating reagent is a compound with Formula III: 
       
         
           
           
               
               
           
         
         wherein: 
         R 4  is selected from the group consisting of tetrafluoroborate, triflate and halogen. 
       
     
     
         4 . A method according to  claim 2 , wherein R 1 , R 2  and R 3  are ethyl groups and R 4  is tetrafluoroborate or triflate. 
     
     
         5 . A method according to  claim 2 , wherein R 1 , R 2  are both methyl, R 3  is aryl and R 4  is tetrafluoroborate or triflate. 
     
     
         6 . A method according to  claim 2 , wherein R 1 , R 2  are both methyl, R 3  is phenyl and R 4  is tetrafluoroborate or triflate. 
     
     
         7 . A method according to  claim 3 , wherein R 4  is triflate or tetrafluoroborate. 
     
     
         8 . A method according to  claim 1 , wherein the pharmaceutically active is a compound of Formula IV: 
       
         
           
           
               
               
           
         
         wherein: R is selected from the group consisting of hydroxyl, furoate and propionate. 
       
     
     
         9 . A method according to  claim 8 , wherein R is propionate or furoate. 
     
     
         10 . A method according to  claim 8 , wherein said monofluoromethylating reagent is reacted with 6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid or 6α,9α-Difluoro-11β-hydroxy, 16α-methyl-3-oxo-17α-(propionyloxy) androsta-1,4-diene-17β-carbothioic acid to give the corresponding compound of formula IV. 
     
     
         11 . A method according to  claim 8 , wherein the compound of formula IV is prepared using S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium tetrafluoroborate salt as monofluoromethylating reagent. 
     
     
         12 . A method according to  claim 8 , wherein the compound of formula IV is prepared using S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium triflate salt as monofluoromethylating reagent. 
     
     
         13 . A method according to  claim 8 , wherein the compound of formula IV is prepared using N-(monofluoromethyl) triethyl ammonium triflate salt as monofluoromethylating reagent. 
     
     
         14 . A method according to  claim 8 , wherein the compound of formula IV is prepared using N-(monofluoromethyl)-N-phenyl-dimethylammonium triflate salt as monofluoromethylating reagent. 
     
     
         15 . A method according to  claim 8 , wherein the compound of formula IV is prepared using N-(monofluoromethyl)-N-phenyl-dimethylammonium tetrafluoroborate salt as monofluoromethylating reagent. 
     
     
         16 . A method according to  claim 8 , wherein the compound of formula IV is prepared using P-monofluoromethyltriphenylphosphonium tetrafluoroborate salt as monofluoromethylating reagent. 
     
     
         17 . A method according to  claim 1 , wherein the preparation of the pharmaceutically active compound comprises an organic solvent. 
     
     
         18 . A method according to  claim 17 , wherein the solvent is selected from the group consisting of acetonitrile, heptane, hexane, cyclohexane, methyl tert-butyl ether (MTBE), dimethylformamide (DMF), toluene, 1,2-dichloromethane, α,α,α-trifluorotoluene, tetrahydrofurane (THF), methyl-THF, 1,2-dimethoxyethane and mixtures thereof. 
     
     
         19 . A method according to  claim 1 , wherein the preparation of the pharmaceutically active compound comprises use of a base. 
     
     
         20 . A method according to  claim 19 , wherein the base is a weak base. 
     
     
         21 . A method according to  claim 19 , wherein the base is an inorganic carbonate. 
     
     
         22 . A method according to  claim 21 , wherein the base is selected from the group consisting of cesium carbonate, sodium carbonate and potassium carbonate, and mixtures thereof. 
     
     
         23 . A method according to  claim 22 , wherein the base is cesium carbonate. 
     
     
         24 . A pharmaceutically active compound, the compound comprising a monofluoromethylating reagent as defined in  claim 1  and containing a “CH 2 F” moiety on a sulphur atom. 
     
     
         25 . The compound according to  claim 24 , wherein the “CH 2 F” moiety is introduced on to a thiol group (S—H) in the preparation of the pharmaceutically active compound. 
     
     
         26 . The compound according to  claim 24 , wherein the said compound is a compound of Formula IV 
       
         
           
           
               
               
           
         
       
       wherein: R is selected from the group consisting of hydroxyl, furoate and propionate. 
     
     
         27 . The compound according to  claim 26 , wherein the organic substrate which is monofluoromethylated comprises a hydroxyl group in its structure.