Process for making estra-4,9(10)-diene steroids

Abstract

A novel process for making estra-4,9(10)-diene-3,17-dione steroids from readily available 19-nor-androst-4-ene-3-one steroids by a straightforward three-step process. Products of this process are important intermediates in the preparation of biologically active substances.

What is claimed is:  
     
         1 . Compounds of formula (II):  
       
         
           
           
               
               
           
         
       
       where X is selected from nothing, C(CH 3 ) 2 , and CH 2 ; R 1  is selected from CH 3 , H, and COOCH 3 ; R 2  is selected from CH 3 , F, and H; and R 3  is selected from CH 3 , OH, F, and H.  
     
     
         2 . Compound of  claim 1  where X═C(CH 3 ) 2  and R 1 ═CH 3 , R 2 ═R 3 ═H.  
     
     
         3 . Compound of formula (IIA):  
       
         
           
           
               
               
           
         
       
     
     
         4 . Compounds of formula (III):  
       
         
           
           
               
               
           
         
       
       where R 1  is selected from CH 3 , H, and COOCH 3 ; R 2  is selected from CH 3 , F, and H; 
 and R 3  is selected from CH 3 , OH, F, and H.  
 
     
     
         5 . Compounds of  claim 4  where R 1 ═CH 3 , R 2 ═R 3 ═H; or where R 1 ═R 2 ═R 3 ═H.  
     
     
         6 . Compounds of formula (IV):  
       
         
           
           
               
               
           
         
       
       where R 1  is selected from CH 3 , H, and COOCH 3 ; R 2  is selected from CH 3 , F, and H; 
 and R 3  is selected from CH 3 , OH, F, and H.  
 
     
     
         7 . Compounds of  claim 6  where R 1 ═CH 3 , R 2 ═R 3 ═H; or where R 1 ═R 2 ═R 3 ═H.  
     
     
         8 . A process for preparation of a steroid having the 4,9(10)-diene-3-one structure, and derivatives thereof, having the formula (VA), which comprises contacting a steroid selected from the group consisting of 10-hydroxy-4-ene-3-ketosteroids (IIIA), 5,10-dihydroxy-3-ketosteroids (IVA), and mixtures of (IIIA) and (IVA), with concentrated sulfuric acid or moderated sulfuric acid, the moderated sulfuric acid comprising a mixture of the concentrated sulfuric acid and water in an amount of up to 5% by volume of the moderated acid, or a mixture of the concentrated sulfuric acid and a second acid in an amount of up to 30% by volume of the moderated acid,  
       
         
           
           
               
               
           
         
       
       where R 1  is selected from CH 3 , H, and COOCH 3 ; and R 2  is selected from CH 3 , F, and H.  
     
     
         9 . A process according to  claim 8  where estra-4,9(10)-diene-3,17-dione (VA) is prepared from a steroid selected from the group consisting of 10-hydroxy-estra-4-ene-3,17-dione (IIIA), 5,10-dihydroxy-estra-3,17-dione (IVA), and mixtures thereof.  
     
     
         10 . A process according to  claim 8  where 7α-methyl-estra-4,9(10)-diene-3,17-dione (VA) is prepared from a steroid selected from the group consisting of 10-hydroxy-7α-methyl-estra-4-ene-3,17-dione (IIIA), 5,10-dihydroxy-estra-3,17-dione (IVA), and mixtures thereof.  
     
     
         11 . A process according to  claim 8  where the steroid is contacted with the concentrated sulfuric acid.  
     
     
         12 . A process for preparation of steroidal estra-4,9(10)-diene-3,17-diones of structure (V):  
       
         
           
           
               
               
           
         
       
       where X is selected from nothing, C(CH 3 ) 2 , and CH 2 ; R 1  is selected from CH 3 , H, and COOCH 3 ; R 2  is selected from CH 3 , F, and H; and R 3  is selected from CH 3 , OH, F, and H; where the process comprises: 
 (a) contacting estra-5(10)-ene-3,17-dione-3,17-bis-ketal (I) with an epoxidizing agent;  
 (b) contacting the epoxide product of step (a) with dilute acid; and  
 (c) contacting the product of step (b) with concentrated sulfuric acid or moderated sulfuric acid, the moderated sulfuric acid comprising a mixture of the concentrated sulfuric acid and water in an amount of up to 5% by volume of the moderated acid, or a mixture of the concentrated sulfuric acid and a second acid in an amount of up to 30% by volume of the moderated acid.  
 
     
     
         13 . A process according to  claim 12  where 7α-methyl-estra-4,9(10)-diene3,17-dione (V) is prepared from a steroid selected from the group consisting of 7α-methyl-estra-5(10)-ene-3,17-dione-3,17-bis-ethylene glycol ketal (I), 7α-methyl-estra-5(10)-ene-3,17-dione-3,17-bis-neopentyl glycolketal (I).  
     
     
         14 . A process according to  claim 12  where the epoxidizing agent is m-chloroperbenzoic acid or peracetic acid.  
     
     
         15 . A process according to  claim 12  where the product of step (b) is contacted with the concentrated sulfuric acid.  
     
     
         16 . A process according to  claim 12  where the product of step (b) is contacted with the moderated sulfuric acid, and where the moderated sulfuric acid comprises a mixture of the concentrated sulfuric acid and concentrated phosphoric acid.  
     
     
         17 . A process according to  claim 12  where estra-4,9(10)-diene-3,17-dione (V) is prepared from a steroid selected from the group consisting of estra-5(10)-ene-3,17-dione-3,17-bis-ethylene glycol ketal (I), estra-5(10)-ene-3,17-dione-3,17-bis-neopentyl glycolketal (I).  
     
     
         18 . A process for preparation of steroidal estra-4,9(10)-diene-3,17-diones of structure (V) by treatment of steroidal estra-5(10),9(11)-diene-3,17-diones of structure (VI) with concentrated mineral acid.  
     
     
         19 . A process according to  claim 18  where the mineral acid is concentrated phosphoric acid.