Method for the preparation of fluticasone and related 17beta-carbothioic esters using a novel carbothioic acid synthesis and novel purification methods

Abstract

This invention discloses a novel method for the conversion of carboxylic acids to carbothioic acids and application of the method to the preparation of androstane carbothiolates, such as fluticasone propionate, which avoids column chromatography.

What is claimed is  
     
         1 . A method for converting a carboxylic acid group to a carbothioic acid group, the method comprising: 
 (a) reacting a compound having the carboxylic group and a first base, an iodide salt, and a compound of formula (4)                        wherein R 7  and R 8  are independently C 1 -C 6  alkyl; or R 7  and R 8  together are C 1 -C 6  alkylene;      (b) reacting the product of step (a) and a hydrolyzing agent; and    (c) reacting the product from step (b) and acid.    
     
     
         2 . The method of  claim 1 , wherein R 7  and R 8  are methyl.  
     
     
         3 . The method of  claim 1 , wherein the first base is a carbonate salt, an amine, or a mixture thereof.  
     
     
         4 . The method of  claim 1 , wherein the iodide salt is an alkali metal iodide, an alkali earth metal iodide, or a tetraalkylammonium iodide.  
     
     
         5 . The method of  claim 1 , wherein the hydrolyzing agent is an alkoxide salt, a thioalkoxide salt, an optionally hydrated sulfide salt, or a mixture thereof.  
     
     
         6 . The method of  claim 1 , wherein the water is present in about one quarter percent by weight to about ten percent by weight of the compound having the carboxylic acid group.  
     
     
         7 . The method of  claim 1 , wherein step (a) is conducted at about 10° C. to about 30° C.  
     
     
         8 . The method of  claim 1 , wherein step (b) is conducted at about −40° C. to about 35° C.  
     
     
         9 . The method of  claim 1 , wherein the acid is hydrochloric, hydrobromic, sulfuric, sulfonic, phosphoric, or trifluoroacetic.  
     
     
         10 . The method of  claim 1 , wherein step (c) is conducted at about −10° C. to about 35° C.  
     
     
         11 . The method of  claim 1  which is conducted as a continuous method.  
     
     
         12 . A method for the conversion of a carboxylic acid group to a carbothioic acid group, the method comprising: 
 (a) reacting a compound having the carboxylic acid group and a first base, an iodide salt, and N,N-dimethylthiocarbamoyl chloride at about 10° C. to about 30° C. in a solvent system comprising an organic component and water, the water present in about one quarter percent by weight to about ten percent by weight of the compound having the carboxylic acid group;    (b) reacting the product from step (a) and an alkoxide salt, a thioalkoxide salt, an optionally hydrated sulfide salt, or a mixture thereof at about −40° C. to about 35° C.; and    (c) reacting the product from step (b) and acid.    
     
     
         13 . A method for dehalogenating a 4-halo-2,3-unsaturated carbonyl group the method comprising: 
 (a) reacting a compound having the 4-halo-2,3-unsaturated carbonyl group, a palladium catalyst, and an additive, optionally in the presence of a reducing agent.    
     
     
         14 . The method of  claim 13 , wherein the palladium catalyst is optionally supported palladium, a palladium(II) salt, a palladium(II) complex, or a palladium(O) complex.  
     
     
         15 . The method of  claim 14 , wherein the palladium catalyst is palladium(II) acetate.  
     
     
         16 . The method of  claim 13 , wherein the additive is a tri(alkyl)phosphine, a tri(cycloalkyl)phosphine, a tri(aryl)phosphine, a tri(heteroaryl)phosphine, a tri(alkyl)phosphite, a tri(cycloalkyl)phosphite, a tri(aryl)phosphite, a tri(heteroaryl)phosphite, or a bidentate phosphine.  
     
     
         17 . The method of  claim 13 , wherein the additive is triphenylphosphine.  
     
     
         18 . The method of  claim 13 , wherein the reducing agent is a borane, a trialkylsilane or a trialkylstannane.  
     
     
         19 . The method of  claim 13  which is conducted in the absence of a reducing agent.  
     
     
         20 . The method of  claim 13  which is conducted in the presence of a reducing agent.  
     
     
         21 . The method of  claim 19  which is conducted at about 50° C. to about 100° C.  
     
     
         22 . The method of  claim 20  which is conducted at about 0° C. to about 35° C.  
     
     
         23 . A method for the preparation of a compound of formula (7)  
       
         
           
           
               
               
           
         
         the symbol  represents a single bond or a double bond; one of R 1  or R 2  is hydrogen and the other is optionally protected hydroxyl; or R 1  and R 2  together are oxo; R 3  and R 4  are independently hydrogen or halide; and R 5  and R 6  are independently C 1 -C 6  alkyl; 
 the method comprising: 
 (c) reacting a compound of formula (3)  
                     
  and a first base, an iodide salt, and the compound of formula (4) to provide a compound of formula (5)  
                     
 (d) reacting the product of step (c) and a hydrolyzing agent to provide a compound of formula (6)  
                     wherein M is Li, Na, or K;    
 (e) optionally reacting the product of step (d) and acid;  
 (f) reacting the product of step (e) and chlorofluoromethane optionally in the presence of a second base; and  
 (g) optionally deprotecting the product of step (f).  
 
 
       
     
     
         24 . The method of  claim 23  further comprising 
 (a) reacting a compound of formula (1)  
                     
  and periodic acid to provide a compound of formula (2)  
                     
 (b) reacting the product of step (a) and an alkanoyl halide and the first base to provide the compound of formula (3)  
                     
 
     
     
         25 . The method of  claim 23 , wherein step (e) is omitted.  
     
     
         26 . The method of  claim 25 , wherein the product of step (d) and chlorofluoromethane are reacted in situ in the absence of the second base.  
     
     
         27 . The method of  claim 23 , wherein R 1  and R 2  are methyl.  
     
     
         28 . The method of  claim 23 , wherein the first base is a carbonate salt, an amine, or a mixture thereof.  
     
     
         29 . The method of  claim 23 , wherein the iodide salt is an alkali metal iodide, an alkali earth metal iodide, or a tetraalkylammonium iodide.  
     
     
         30 . The method of  claim 23 , wherein the hydrolyzing agent is an alkoxide salt, a thioalkoxide salt, an optionally hydrated sulfide salt, or a mixture thereof.  
     
     
         31 . The method of  claim 23 , wherein the second base is a carbonate salt.  
     
     
         32 . The method of  claim 23 , wherein step (c) is conducted in a solvent comprising an organic component and water, the water present in about one quarter percent by weight to about ten percent by weight of the starting material.  
     
     
         33 . The method of  claim 32 , wherein the organic component is a C 2 -C 5  alkylamide, a C 4 -C 6  dialkoxyalkyl, a C 1 -C 4  alcohol, a C 1 -C 4  haloalkyl a C 3 -C 10  ketone, or a mixture thereof.  
     
     
         34 . The method of  claim 23 , wherein step (d) is conducted in a C 2 -C 5  alkylamide.  
     
     
         35 . The method of  claim 23 , wherein step (c) is conducted at about 0° C. to about 40° C.  
     
     
         36 . The method of  claim 23 , wherein step (d) is conducted at about −40° C. to about 35° C.  
     
     
         37 . The method of  claim 23 , wherein step (e) is conducted at about −10° C. to about 30° C.  
     
     
         38 . The method of  claim 23  which is conducted as a continuous method.  
     
     
         39 . The method of  claim 24 , wherein the compound of formula (1) is commercial grade flumethasone; 
 the compound of formula (2) is 6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid;    the compound of formula (3) is 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta-1,4-diene-17β-carboxylic acid;    the compound of formula (5) is 17β-(N,N-(dimethylcarbamoyl)thio)carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene; and    the compound of formula (7) is 6α,9α-difluoro-17α-(((fluoromethyl)sulfanyl)-carbonyl)-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-dien-17α-yl propionate.    
     
     
         40 . The method of  claim 39  further comprising purification of the compound of formula (3) by recrystallization from water, a C 3 -C 20  ketone, or a mixture thereof.  
     
     
         41 . The method of  claim 40 , wherein the purification comprises recrystallization from a mixture of water, 2-butanone, and 3-pentanone.  
     
     
         42 . The method of  claim 41 , wherein the product which is purified by recrystallization is further purified by repeated recrystallization.  
     
     
         43 . The method of  claim 42 , wherein the repeated recrystallization is conducted in a mixture of water, 2-butanone, and 3-pentanone.  
     
     
         44 . The method of  claim 39  further comprising reacting the compound formula (1), the compound of formula (2), the compound of formula (3), the compound of formula (5), or the compound of formula (7) with a palladium catalyst and an additive, optionally in the presence of a reducing agent.  
     
     
         45 . The method of  claim 44 , wherein the compound which is reacted with the palladium catalyst and the additive is the compound of formula (1).  
     
     
         46 . The method of  claim 44 , wherein the palladium catalyst is optionally supported palladium, a palladium(II) salt, a palladium(II) complex or a palladium(O) complex.  
     
     
         47 . The method of  claim 46 , wherein the palladium catalyst is present in about 0.3 mole % to about 5 mole % of the compound of formula (1).  
     
     
         47 . The method of  claim 46 , wherein the palladium catalyst is palladium(II) acetate.  
     
     
         48 . The method of  claim 44 , wherein the additive is a tri(alkyl)phosphine, a tri(cycloalkyl)phosphine, a tri(aryl)phosphine, a tri(heteroaryl)phosphine, a tri(alkyl)phosphite, a tri(cycloalkyl)phosphite, a tri(aryl)phosphite, a tri(heteroaryl)phosphite, or a bidentate phosphine.  
     
     
         49 . The method of  claim 48 , wherein the addative is present in about 0.8 mol % to about 15 mol % of the compound of formula (1).  
     
     
         50 . The method of  claim 48 , wherein the additive is triphenylphosphine.  
     
     
         51 . The method of  claim 44  which is conducted in the absence of a reducing agent.  
     
     
         52 . The method of  claim 44  which is conducted in the presence of the reducing agent.  
     
     
         53 . The method of  claim 52 , wherein the reducing agent is a borane, a trialkylsilane, or a trialkylstannane.  
     
     
         54 . The method of  claim 53 , wherein the reducing agent is present in about 1 mol % to about 30 mol % of the compound of formula (1).  
     
     
         55 . The method of  claim 53 , wherein the reducing agent is triethylsilane.  
     
     
         56 . The method of  claim 51  which is conducted at about 50° C. to about 100° C.  
     
     
         57 . The method of  claim 52  which is conducted at about 0° C. to about 35° C.  
     
     
         58 . The method of  claim 44 , wherein the solvent in which the reaction is conducted is a C 2 -C 5  alkylamide, a C 4 -C 6  dialkoxyalkyl, an optionally substituted aromatic hydrocarbon, a C 1 -C 4  haloalkyl a C 3 -C 10  ketone, or a mixture thereof.  
     
     
         59 . The method of  claim 58  which is conducted in a C 2 -C 5  alkylamide.  
     
     
         60 . The method of  claim 45  further comprising purification of the compound of formula (3) by recrystallization from water, a C 3 -C 20  ketone, or a mixture thereof.  
     
     
         61 . The method of  claim 60 , wherein the purification comprises recrystallization from a mixture of water, 2-butanone, and 3-pentanone.  
     
     
         62 . A method for the preparation of a compound of formula (7)  
       
         
           
           
               
               
           
         
         the symbol  represents a single bond or a double bond; one of R 1  or R 2  is hydrogen, and the other is optionally protected hydroxyl, or R 1  and R 2  together are oxo; R 3  and R 3  are independently hydrogen or halide; and R 5  and R 6  are independently C 1 -C 6  alkyl; 
 the method comprising: 
 (c) reacting a compound of formula (3)  
                     
  and N,N-dimethylthiocarbamoyl chloride in the presence of a first base and an iodide salt at about 10° C. to about 30° C. in a solvent system comprising a C 2 -C 5  alkylamide, a C 4 -C 6  dialkoxyalkyl, a C 1 -C 4  alcohol, a C 3 -C 10  ketone, or a mixture thereof and water, the water present in about one quarter percent by weight to about ten percent by weight of the compound of formula (3) to provide a compound of formula (5),  
                     wherein R 7  and R 8  are methyl;    
 (d) reacting the product from step (a) and an alkoxide salt, a thioalkoxide salt, an optionally hydrated sulfide salt, or a mixture thereof at about −40° C. to about 35° C., to provide a compound of formula (6)  
                     
 (e) reacting the product from step (b) and chlorofluoromethane at about −10° C. to about 30° C.  
 
 
       
     
     
         63 . The method of  claim 62  further comprising 
 (a) reacting a compound of formula (1)  
                     
  and periodic acid to provide a compound of formula (2)  
                     
 (b) reacting the product of step (a) and an alkanoyl halide and the first base to provide the compound of formula (3)  
                     
 
     
     
         64 . The method of  claim 63  further comprising reacting the compound formula (1) with palladium(II) acetate and triphenylphosphine at a temperature of about 50° C. to about 100° C.  
     
     
         65 . A method for the preparation of 6α,9α-difluoro-17β-(((fluoromethyl)-sulfanyl)carbonyl)-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-dien-17α-yl propionate, the method comprising: 
 (c) reacting 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta-1,4-diene-17β-carboxylic acid and a first base, an iodide salt, and N,N-dimethylthiocarbamoyl chloride at about 10° C. to about 30° C. in a solvent system comprising an organic component and water, the water present in about one quarter percent by weight to about ten percent by weight of the 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta-1,4-diene-17β-carboxylic acid, to provide 17β-(N,N-(dimethylcarbamoyl)thio)carbonyl-6α,9α-difluoro-11β-hydroxy-16-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene;  
 (d) reacting the product from step (a) and an alkoxide salt, a thioalkoxide salt, an optionally hydrated sulfide salt, or a mixture thereof at about −40° C. to about 35° C., to provide a 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)-androsta-1,4-diene-17-carbothiolate salt;  
 (e) reacting the product from step (b) and chlorofluoromethane at about −10° C. to about 30° C.  
 
     
     
         66 . The method of  claim 65  further further comprising 
 (a) reacting commercial grade flumethasone and periodic acid to provide 6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid and  
 (b) reacting the product of step (a), propionyl chloride, and the first base to provide 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta-1,4-diene-17β-carboxylic acid.  
 
     
     
         67 . The method of  claim 65  further comprising reacting the commercial grade flumethasone with about 0.3 mole % to about 5 mole % palladium(II) acetate and about 0.8 mole % to about 15 mole % triphenylphosphine at a temperature of about 50° C. to about 100° C.