Process for the Preparation of Fluticasone Propionate

Abstract

The present invention relates to a process for the preparation of steroidal 17β-carboxylic thioates. More particularly the present invention relates to a convenient and efficient synthesis of steroidal 17β-carboxylic thioates, such as fluticasone propionate I, using soluble mixed fluorides to introduce fluorine by displacing an appropriate leaving group X in compounds II resulting in selective and controlled fluorination. The present invention also relates to intermediates II and their preparation.

1 - 8 . (canceled) 
     
     
         9 . A process of purifying a compound II 
       
         
           
           
               
               
           
         
       
       wherein X is a leaving group, comprising crystallising compound II using a solvent system comprising a polar and a non-polar solvent. 
     
     
         10 - 21 . (canceled) 
     
     
         22 . The process of  claim 9 , wherein the leaving group X is:
 (a) a bromo, iodo, benzenesulphonyl, p-toluenesulphonyl (tosyl), methylsulphonyl (mesyl), trifluoromethanesulphonyl (triflate), or OCOCH 3  group; or   (b) iodo or bromo; or   (c) iodo.   
     
     
         23 . The process of  claim 9 , wherein the polar solvent comprises formic acid, acetic acid, propionic acid, butyric acid or methanol. 
     
     
         24 . The process of  claim 9 , wherein the solvent system comprises:
 (a) ethyl acetate, butyl acetate, methyl acetate, isopropyl acetate, methanol, acetone, THF, dimethylformamide, dimethylacetamide, methyl acetate/formic acid, methyl acetate/acetic acid, ethyl acetate/acetic acid, isopropyl acetate/acetic acid, butyl acetate/acetic acid, ethyl acetate/propionic acid, or ethyl acetate/butyric acid; or   (b) ethyl acetate and acetic acid.   
     
     
         25 . The process of  claim 9 , wherein:
 (a) the compound II obtained comprises less than 0.4% of dimer impurities 17,17′-(disulphanediyldicarbonyl)bis(6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17α-yl)dipropionate 11 and 17,17′-(trisulphanediyldicarbonyl)bis(6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17α-yl)dipropionate 12; or   (b) the HPLC purity of the compound II obtained is greater than 95%; or   (c) the yield of the compound II obtained is greater than 60%.   
     
     
         26 . The process of  claim 9 , wherein the compound II is prepared by a process comprising converting a compound III 
       
         
           
           
               
               
           
         
       
       wherein Y is another leaving group, into compound II in the presence of a radical inhibitor or an antioxidant or both. 
     
     
         27 . The process of  claim 26 , wherein the leaving group Y is:
 (a) a chloro, bromo or hydroxyl group; or   (b) chloro.   
     
     
         28 . The process of  claim 26 , wherein:
 (a) the radical inhibitor is selected from methylhydroquinone, bis(4-methoxy-3-tert-butyl-5-methyl-phenyl)sulphide, cyclohexene, L-cysteine, N,N-dimethylglycine, sorbic acid and hydroquinone; or   (b) the radical inhibitor is hydroquinone; or   (c) the antioxidant is selected from ascorbic acid, potassium metabisulphite, sodium metabisulphite, sodium thiosulphate, butylated hydroxyanisole and butylated hydroxytoluene; or   (d) the antioxidant is butylated hydroxytoluene; or   (e) the conversion is carried out in presence of hydroquinone and butylated hydroxytoluene.   
     
     
         29 . The process of  claim 26 , wherein:
 (a) the compound II obtained by the conversion comprises less than 0.5% of dimer impurities 17,17′-(disulphanediyldicarbonyl)bis(6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17α-yl)dipropionate 11 and 17,17′-(trisulphanediyldicarbonyl)bis-(6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17α-yl)dipropionate 12; or   (b) the HPLC purity of the compound II obtained by the conversion is greater than 95%; or   (c) the yield of the compound II obtained by the conversion is greater than 60%.   
     
     
         30 . A process of preparing S-fluoromethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioate I 
       
         
           
           
               
               
           
         
       
       comprising the use of compound II prepared by a process as claimed in  claim 9 . 
     
     
         31 . The process of  claim 30 , wherein soluble mixed fluorides are used to fluorinate the compound II. 
     
     
         32 . The process of  claim 31 , wherein the soluble mixed fluorides:
 (a) are selected from potassium fluoride, caesium fluoride, antimony fluoride, tetrabutyl ammonium fluoride, calcium fluoride, silver fluoride, bis(2-methoxyethyl)aminosulphur trifluoride (DEOXO-FLUOR®), diethylaminosulphur trifluoride (DAST®), and hexafluoropropyldiethylamine (MEC-81®); or   (b) are selected from potassium fluoride, caesium fluoride, antimony fluoride, tetrabutyl ammonium fluoride, calcium fluoride, and silver fluoride; or   (c) comprise silver fluoride and at least one other fluoride; or   (d) comprise or are silver fluoride and calcium fluoride; or   (e) are a solution of soluble mixed fluorides in an organic solvent; or   (f) are a solution of soluble mixed fluorides in an organic solvent, and wherein the solution of soluble mixed fluorides is prepared by heating the soluble mixed fluorides in the organic solvent at a temperature of 25-95° C.; or   (g) are a solution of silver fluoride and calcium fluoride in an organic solvent; or   (h) are a solution of silver fluoride and calcium fluoride in an organic solvent, and wherein the solution of soluble mixed fluorides is prepared by heating the soluble mixed fluorides in the organic solvent at a temperature of 25-95° C.   
     
     
         33 . The process of  claim 32 , wherein the organic solvent:
 (a) is selected from acetonitrile, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethylacetamide, and a combination of ethyl acetate and acetonitrile, benzonitrile or propionitrile; or   (b) comprises or is acetonitrile.   
     
     
         34 . The process of  claim 31 , wherein:
 (a) the process further comprises the step of crystallising compound I from an alcohol; or   (b) the compound I obtained comprises less than 0.4% of dimer impurities 17,17′-(disulphanediyldicarbonyl)bis(6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17α-yl)dipropionate 11 and 17,17′-(trisulphanediyldicarbonyl)bis(6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17α-yl)dipropionate 12; or   (c) the HPLC purity of the compound I obtained is greater than 97%; or   (d) the yield of the compound I obtained is greater than 60%.   
     
     
         35 . A compound II 
       
         
           
           
               
               
           
         
       
       wherein X is a leaving group, obtainable by a process as claimed in  claim 9 . 
     
     
         36 . The compound II of  claim 35 , wherein the leaving group X is:
 (a) a bromo, iodo, benzenesulphonyl, p-toluenesulphonyl (tosyl), methylsulphonyl (mesyl), trifluoromethanesulphonyl (triflate), or OCOCH 3  group; or   (b) iodo or bromo; or   (c) iodo.   
     
     
         37 . A process of preparing S-fluoromethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioate I 
       
         
           
           
               
               
           
         
       
       comprising the use of compound II as claimed in  claim 35 . 
     
     
         38 . The process of  claim 37 , wherein soluble mixed fluorides are used to fluorinate the compound II. 
     
     
         39 . The process of  claim 38 , wherein:
 (a) the process further comprises the step of crystallising compound I from an alcohol; or   (b) the compound I obtained comprises less than 0.4% of dimer impurities 17,17′-(disulphanediyldicarbonyl)bis(6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17α-yl)dipropionate 11 and 17,17′-(trisulphanediyldicarbonyl)bis(6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17α-yl)dipropionate 12; or   (c) the HPLC purity of the compound I obtained is greater than 97%; or   (d) the yield of the compound I obtained is greater than 60%.   
     
     
         40 . A compound II 
       
         
           
           
               
               
           
         
       
       wherein X is a leaving group, which has an HPLC purity of greater than 95%, or greater than 97%, or greater than 98%, or greater than 99%, or greater than 99.5%. 
     
     
         41 . The compound II of  claim 40 , wherein the leaving group X is:
 (a) a bromo, iodo, benzenesulphonyl, p-toluenesulphonyl (tosyl), methylsulphonyl (mesyl), trifluoromethanesulphonyl (triflate), or OCOCH 3  group; or   (b) iodo or bromo; or   (c) iodo.   
     
     
         42 . A process of preparing S-fluoromethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioate I 
       
         
           
           
               
               
           
         
       
       comprising the use of compound II as claimed in  claim 40 . 
     
     
         43 . The process of  claim 42 , wherein soluble mixed fluorides are used to fluorinate the compound II. 
     
     
         44 . The process of  claim 43 , wherein:
 (a) the process further comprises the step of crystallising compound I from an alcohol; or   (b) the compound I obtained comprises less than 0.4% of dimer impurities 17,17′-(disulphanediyldicarbonyl)bis(6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17α-yl)dipropionate 11 and 17,17′-(trisulphanediyldicarbonyl)bis(6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17α-yl)dipropionate 12; or   (c) the HPLC purity of the compound I obtained is greater than 97%; or   (d) the yield of the compound I obtained is greater than 60%.