Processes for preparations of 9,11-epoxy steroids and intermediates useful therein

Abstract

Multiple novel reaction schemes, novel process steps and novel intermediates are provided for the synthesis of 9,11-epoxy steroids.

1 . A process for the preparation of a compound of Formula II:  
     
       
         
         
             
             
         
       
       wherein  
       -A-A- represents the group —CHR 4 —CHR 5 — or —CR 4 ═CR 5 —;  
       R 3 , R 4  and R 5  are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy carbonyl, cyano and aryloxy;  
       R 1  represents an alpha-oriented lower alkoxycarbonyl or hydroxycarbonyl radical;  
       —B—B— represents the group —CHR 6 —CHR 7 — or an alpha- or beta-oriented group:  
       
         
           
           
               
               
           
         
       
       where R 6  and R 7  are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy; and  
       R 8  and R 9  are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy, or R 8  and R 9  together comprise a carbocyclic or heterocyclic ring structure, or R 8  or R 9  together with R 6  or R 7  comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring;  
       the process comprising:  
       removing an IIα-leaving group from a compound of Formula IV:  
       
         
           
           
               
               
           
         
       
       wherein -A-A-, —B—B—, R 1 , R 3 , R 8 , and R 9  are as defined above, and R 2  is a leaving group the abstraction of which is effective for generating a double bond between the 9- and 11-carbon atoms.  
     
   
   
       2 . A process as set forth in  claim 1  wherein said compound of Formula II corresponds to Formula IIAA:  
     
       
         
         
             
             
         
       
     
     wherein: 
 -A-A- represents the group —CH 2 —CH 2 — or —CH═CH—;  
 —B—B— represents the group —CH 2 —CH 2 — or an alpha- or beta-oriented group of Formula IIIA:  
                     
 R 1  represents an alpha-oriented lower alkoxycarbonyl radical;  
 X represents two hydrogen atoms or oxo;  
 Y 1  and Y 2  together represent the oxygen bridge -0-, or  
 Y 1  represents hydroxy, and  
 Y 2  represents hydroxy, lower alkoxy or, if X represents H 2 , also lower alkanoyloxy;  
 and salts of compounds in which X represents oxo and Y 2  represents hydroxy, the process comprising:  
 contacting a solution comprising a lower alkanoic acid and a salt of a lower alkanoic acid with a compound corresponding to Formula IVAA:  
                     
 wherein -A-A-, —B—B—, R 1 , X, y 1  and Y 2  are as defined in Formula IIAA, and R 2  is lower alkylsulfonyloxy or acyloxy.  
 
   
   
       3 . A process as set forth in  claim 1  wherein said compound of Formula IV is Methyl Hydrogen 17α-Hydroxy-11α-(methylsulfonyl)oxy-3-oxopregn-4-ene-7α,21-dicarboxylate, γ-Lactone and said compound of Formula II is Methyl Hydrogen 17α-Hydroxy-3-oxopregna-4,9(11)-diene-7α,21-dicarboxylate, γ-Lactone.  
   
   
       4 . A process for the preparation of a compound of Formula IV:  
     
       
         
         
             
             
         
       
     
     wherein 
 -A-A- represents the group —CHR 4 —CHR 5 — or —CR 4 ═CR 5 —;  
 R 3 , R 4  and R 5  are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy carbonyl, cyano and aryloxy;  
 R 1  represents an alpha-oriented lower alkoxycarbonyl or hydroxycarbonyl radical;  
 —B—B— represents the group —CHR 6 —CHR 7 — or an alpha or beta-oriented group:  
                     
 where R 6  and R 7  independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy; and  
 R 8  and R 9  are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy, or R 8  and R 9  together comprise a carbocyclic or heterocyclic ring structure, or R 8  or R 9  together with R 6  or R 7  comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring; and  
 R 2  is lower alkylsulfonyloxy or acyloxy or a halide;  
 the process comprising:  
 reacting a lower alkylsulfonylating or acylating reagent or a halide generating agent such as thionyl halide, sulfuryl halide, or oxalyl halide with a compound of Formula V  
                     
 wherein -A-A-, —B—B—, R 1 , R 3 , R 8 , and R 9  are as defined above.  
 
   
   
       5 . A process as set forth in  claim 4  wherein said compound of Formula IV corresponds to Formula IVAA:  
     
       
         
         
             
             
         
       
     
     wherein: 
 -A-A- represents the group —CH 2 —CH 1 — or —CH═CH—;  
 R 1  represents an alpha-oriented lower alkoxycarbonyl radical;  
 R 2  represents lower alkylsulfonyloxy or acyloxy;  
 B—B— represents the group —CH 2 —CH 2 — or an alpha- or beta-oriented group:  
                     
 X represents two hydrogen atoms or oxo;  
 Y 1  and Y 2  together represent the oxygen bridge -0-, or  
 Y 1  represents hydroxy, and  
 Y 2  represents hydroxy, lower alkoxy or, if X represents H 2  also lower alkanoyloxy;  
 and salts of compounds in which X represents oxo and Y 2  represents hydroxy, the process comprising:  
 reacting a lower alkylsulfonyl or acyl halide in the presence of a hydrogen halide scavenger with a compound corresponding to the formula:  
                     
 wherein -A-A-, —B—B—, R 1 , X, Y 1  and Y 2  are as defined in Formula IVAA.  
 
   
   
       6 . A process as set forth in  claim 4  wherein said compound of Formula IV is Methyl Hydrogen 17α-Hydroxy-11α-(methylsulfonyl)oxy-3-oxopregn-4-ene-7α,21-dicarboxylate, γ-Lactone and said compound of Formula V is Methyl Hydrogen 11α,17α-Dihydroxy-3-oxopregn-4-ene-7α,21-dicarboxylate, γ-Lactone.  
   
   
       7 . A process for the preparation of a compound of Formula V:  
     
       
         
         
             
             
         
       
     
     wherein 
 -A-A- represents the group —CHR 4 —CHR 5 — or —CR 4 ═CR 5 —;  
 R 3 , R 4  and R 5  are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy;  
 R 1  represents an alpha-oriented lower alkoxycarbonyl or hydroxycarbonyl radical;  
 —B—B— represents the group —CHR 5 —CHR 7 — or an alpha or beta-oriented group:  
                     
 where R 6  and R 7  are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy; and  
 R 8  and R 9  are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy, or R 8  and R 9  together comprise a carbocyclic or heterocyclic ring structure, or R 8  or R 9  together with R 6  or R 7  comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring;  
 the process comprising:  
 reacting a compound of Formula VI with an alkali metal alkoxide corresponding to the formula R 10 OM wherein M is alkali metal and R 10 OM- corresponds to the alkoxy substituent of R1, said compound of Formula VI having the structure:  
                     
 wherein -A-A-, —B—B—, R 3 , R 8 , and R 9  are as defined above.  
 
   
   
       8 . A process as set forth in  claim 7  wherein the compound of Formula VA corresponds to the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 -A-A- represents the group —CH 2 —CH 2 — or —CH═CH—;  
 R 1  represents an alpha-oriented lower alkoxycarbonyl radical;  
 —B—B— represents the group —CH 2 —CH 2 — or an alpha- or beta-oriented group:  
                     
 X represents two hydrogen atoms or oxo;  
 Y 1  and Y 2  together represent the oxygen bridge -0-, or  
 Y 1  represents hydroxy, and  
 Y 2  represents hydroxy, lower alkoxy or, if X represents H 2 , also lower alkanoyloxy;  
 and salts of compounds in which X represents oxo and Y 2  represents hydroxy, the process comprising:  
 reacting a compound of Formula VIM with an alkali metal alkoxide corresponding to the formula R 10 OM in the presence of an alcohol having the formula R 10 OH, wherein M is alkali metal and R 10 O— corresponds to the alkoxy substituent of R 1 , said compound of Formula VIAA having the structure:  
                     
 wherein -A-A-, —B—B—, Y 1 , Y 2  and X are as defined in Formula VAA.  
 
   
   
       9 . A process as set forth in  claim 7  wherein the compound of Formula V is Methyl Hydrogen IIa,17a Dihydroxy-3-oxopregn-4-ene-7α,21-dicarboxylate, γ-Lactone and the compound of Formula VI is 4′S(4′α),7′α Hexadecahyadro-11′α-hydroxy-10′β,13′β-dimethyl-3′,5,20′-trioxospiro[furan-1(3H), 17′β-[4,7]methano[17H]cyclopenta[a]phenanthrene]-5′β(2′H)-carbonitrile.  
   
   
       10 . A process as set forth in  claim 7  wherein cyanide ion is formed as a by-product of the reaction, the process further comprising removal of cyanide ion from the reaction zone during the reaction to reduce the extent of any reaction of cyanide ion with the product of Formula V.  
   
   
       11 . A process as set forth in  claim 10  wherein cyanide ion is removed from the reaction by precipitation with a precipitating agent.  
   
   
       12 . A process as set forth in  claim 11  wherein said reaction is carried out in a solvent medium, and said precipitating agent comprises a salt comprising a cation which forms a cyanide compound of lower solubility in said medium than the solubility of the precipitating agent therein.  
   
   
       13 . A process as set forth in  claim 12  wherein said cation is selected from the group consisting of alkaline earth metal ions and transition metal ions.  
   
   
       14 . A process for the preparation of a compound of Formula VI:  
     
       
         
         
             
             
         
       
     
     wherein 
 -A-A- represents the group —CHR 4 —CHR 5 — or —CR 4 ═CR 5 —;  
 R 3 , R 4  and R 5  are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy;  
 —B—B— represents the group —CHR 6 —CHR 7 — or an alpha or beta-oriented group:  
                     
 where R 6  and R 7  are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy; and  
 R 8  and R 9  are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy, or R 8  and R 9  together comprise a carbocyclic or heterocyclic ring structure, or R 8  or R 9  together with R 6  or R 7  comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring;  
 the process comprising:  
 hydrolyzing a compound corresponding to Formula VIII:  
                     
 wherein -A-A-, —B—B—, R 3 , R 8 , and R 9  are as defined above.  
 
   
   
       15 . A process as set forth in  claim 14  wherein said compound of Formula VI corresponds to the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 -A-A- represents the group —CH 2 —CH 2 — or —CH═CH—;  
 —B—B— represents the group —CH 2 —CH 2 — or an alpha- or beta-oriented group:  
                     
 X represents two hydrogen atoms or oxo;  
 Y 1  and Y 2  together represent the oxygen bridge -0-, or  
 Y 1  represents hydroxy, and  
 Y 2  represents hydroxy, lower alkoxy or, if X represents H 2 , also lower alkanoyloxy;  
 and salts of compounds in which X represents oxo and Y 2  represents hydroxy, the process comprising:  
 hydrolyzing a compound of Formula VIIAA in the presence of an acid and an organic solvent and/or water, said compound of Formula VIIAA having the structure:  
                     
 wherein -A-A-, —B—B—, Y 1  Y 2  and X are as defined in Formula VIAA.  
 
   
   
       16 . A process as set forth in  claim 14  wherein said compound of Formula VI is 4′S(4′α),7′αa-Hexadecahydro 11′α-hydroxy-10′β,13′β-dimethyl-3′,5,20′-trioxospiro[furan-2(3H),17′β-[4,7]methano[17H]cyclopenta[a]phenanthrene]-5′β(2′H)-carbonitrile and said compound of Formula VII is 5′R(5′α),7′β-20′-Aminohexadecahydro-11′β-hydroxy-10′α,13′α-dimethyl-3′,5-dioxospiro[furan-2(3H),17′α(S′H)-[7,4]metheno[4H]cyclopenta[a]phenanthrene]-5′-carbonitrile.  
   
   
       17 . A process for the preparation of a compound of Formula VII:  
     
       
         
         
             
             
         
       
     
     wherein 
 -A-A- represents the group —CHR 4 —CHR 5 — or —CR 4 ═CR 5 —;  
 R 3 , R 4  and R 5  are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, cyano and aryloxy;  
 —B—B— represents the group —CHR6-CHR7- or an alpha- or beta-oriented group:  
                     
 where R 6  and R 7  are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy; and  
 R 8  and R 9  are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy, or R 8  and R 9  together comprise a carbocyclic or heterocyclic ring structure, or R 8  or R 9  together with R 6  or R 7  comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring;  
 the process comprising:  
 reacting a compound of Formula VIII with a source of cyanide ion in the presence of an alkali metal salt, said compound of Formula VIII having the structure:  
                     
 wherein -A-A-, —B—B—, R 3 , R 8 , and R 9  are as defined above.  
 
   
   
       18 . A process as set forth in  claim 17  wherein said compound of Formula VII corresponds to Formula VIIAA:  
     
       
         
         
             
             
         
       
     
     wherein: 
 -A-A- represents the group —CH 2 —CH 2 — or —CH═CH—;  
 —B—B— represents the group —CH 2 —CH 2 — or an alpha- or beta-oriented group:  
                     
 X represents two hydrogen atoms or oxo;  
 Y 1  and Y 2  together represent the oxygen bridge -0-, or  
 Y 1  represents hydroxy, and  
 Y 2  represents hydroxy, lower alkoxy or, if X represents H 2 , also lower alkanoyloxy;  
 and salts of compounds in which X represents oxo and Y 2  represents hydroxy, the process comprising:  
 reacting a cyanide source such as ketone cyanohydrin in the presence of an alkali metal salt such as LiCl and in the presence of a base with an 11a-hydroxy compound corresponding to the formula:  
                     
 wherein -A-A-, —B—B—, Y 1 , Y 2 , and X are as defined in Formula VIIAA.  
 
   
   
       19 . A process as set forth in  claim 17  wherein said compound of Formula VII is 5′R(5′α),7′β-20′-Aminohexadecahydro-11′β-hydroxy-10′α,13′α-dimethyl-3′,5-dioxospiro[furan-2(3H),17′α(5′H)-[7,4]metheno[4H]cyclopenta[a]phenanthrene]-5′-carbonitrile and said compound of Formula VIII is IIα,I7α-Dihydroxy-3-oxopregna-4,6-diene-21-carboxylic Acid, γ-Lactone.  
   
   
       20 . A process as set forth in  claim 17  wherein said source of cyanide ion comprises an alkali metal cyanide, the reaction between said compound of Formula VIII and cyanide ion being carried out in the presence of an acid and water.  
   
   
       21 .- 152 . (canceled)