Process for the production of 3-oxo-pregn-4-ene-21, 17-carbolactones by the metal-free oxidation of 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanes

Abstract

This invention relates to processes for the production of 3-oxo-pregnane-21,17-carbolactones of formula II as well as 3-oxo-pregn-4-ene-21,17-carbolactones of formula III by the metal-free oxidation of 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanes of formula I In addition, the invention relates to the dichioromethane hemisolvate of 6β,7β;15β,16β-dimethylene-3-oxo-17α-pregnan-5β-ol-21,17-carbolactone (IV) as such as well as to a process for the production of drospirenone.

1 . Process for the production of 3-oxo-pregnane-21,17-carbolactones of formula II  
       
         
           
           
               
               
           
         
       
       in which 
 R 5  is hydrogen, hydroxy;  
 R 6a  is hydrogen, together with R 5  a double bond, or together with R 7a  a —CH 2  group;  
 R 6b  is hydrogen, together with R 7b  a —CH 2  group or a double bond;  
 R 7a  is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -thioacyl or together with R 6a  a —CH 2  group,  
 R 7b  is hydrogen, or together with R 6b  a —CH 2  group;  
 R 9  is hydrogen, together with R 11  a double bond, or together with R 11  an epoxy group -O-;  
 R 10  is hydrogen, methyl, or ethyl;  
 R 11  is hydrogen, together with R 9  a double bond or together with R 9  an epoxy group -O-;  
 R 13  is hydrogen, methyl or ethyl;  
 R 15  is hydrogen, C 1 -C 4 -alkyl, together with R 16  a —CH 2  group or a double bond;  
 R 16  is hydrogen, together with R 15  a —CH 2  group or a double bond;  
 comprising the reaction of compounds of formula I  
                     
 with at least 3 molar equivalents of an organic or inorganic hypochlorite as oxidizing agent in the presence of catalytic amounts of a 2,2,6,6-tetramethylpiperidine -N-oxide derivative at a pH of at least 8.0.  
 
     
     
         2 . Process according to  claim 1  for the production of 3-oxo-17α-pregnane-21,17-carbolactones of formula IIa  
       
         
           
           
               
               
           
         
       
       in which 
 R 6a  is hydrogen or together with R 7a  a —CH 2  group:  
 R 6b  is hydrogen, together with R 7b  a —CH 2  group, or a double bond;  
 R 7a  is hydrogen, C 1 -C 4 -alkoxycarbonyl, or C 1 -C 4 -thioacyl;  
 R 7b  is hydrogen, or together with R 6b  a —CH 2  group,  
 R 9  is hydrogen, together with R 11  a double bond or together with R 11  an epoxy group —O—;  
 R 10  is hydrogen, or methyl;  
 R 11  is hydrogen, together with R 9  a double bond or together with R 9  an epoxy group -O-;  
 R 15  is hydrogen, together with R 16  a —CH 2  group or a double bond;  
 R 16  is hydrogen, together with R 15  a —CH 2  group or a double bond;  
 wherein compounds of formula Ia  
                     
 are reacted.  
 
     
     
         3 . Process according to  claim 1  for the production of the compound of formula IIb,  
       
         
           
           
               
               
           
         
       
       whereby the compound of formula Ib  
       
         
           
           
               
               
           
         
       
       is used as a starting material.  
     
     
         4 . Process for the production of 3-oxo-pregn-4-ene-21,17-carbolactones of formula III  
       
         
           
           
               
               
           
         
       
       in which 
 R 6a  is hydrogen, together with R 5  a double bond, or together with R 7a  a —CH 2  group;  
 R 6b  is hydrogen, together with R 7b  a —CH 2  group or a double bond;  
 R 7a  is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -thioacyl or together with R 6a  a —CH 2  group,  
 R 7b  is hydrogen, or together with R 6b  a —CH 2  group;  
 R 9  is hydrogen, together with R 11  a double bond, or together with R 11  an epoxy group -O-;  
 R 10  is hydrogen, methyl, or ethyl;  
 R 11  is hydrogen, together with R 9  a double bond or together with R 9  an epoxy group -O-;  
 R 13  is hydrogen, methyl or ethyl;  
 R 15  is hydrogen, C 1 -C 4 -alkyl, together with R 16  a —CH 2  group or a double bond,  
 R 16  is hydrogen, together with R 15  a —CH 2  group or a double bond; comprising the following steps:  
 a) the reaction of compounds of general formula I  
                     
 in which  
 R 5  is hydroxy;  
 R 6a , R 6b , R 7a , R 7b , R 10 , R 11 , R 13 , R 15 , R 16  have the same meaning as in formula III,  
 with at least 3 molar equivalents of an organic or inorganic hypochlorite as an oxidizing agent in the presence of 1-5mol % of a 2,2,6,6-tetramethyl-piperidine-N-oxide derivative at a pH of at least 8.0 and at a temperature of 0-15° C., in dichloromethane or in a two-phase dichloromethane-water mixture,  
 to form the compounds of formula II  
                     
 b) subsequent elimination of water at pH<5, optionally in the presence of an acid.  
 
     
     
         5 . Process for the production of 3-oxo-pregn-4-ene-21,17-carbolactones of formula III  
       
         
           
           
               
               
           
         
       
       in which 
 R 6a  is hydrogen, together with R 5  a double bond, or together with R 7a  a —CH 2  group;  
 R 6b  is hydrogen, together with R 7b  a —CH 2  group or a double bond;  
 R 7a  is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -thioacyl or together with R 6a  a —CH 2  group,  
 R 7b  is hydrogen, or together with R 6b  a —CH 2  group; R 9  is hydrogen, together with R 11  a double bond, or together with R 11  an epoxy group -O-;  
 R 10  is hydrogen, methyl, or ethyl;  
 R 11  is hydrogen, together with R 9  a double bond or together with R 9  an epoxy group —O—;  
 R 13  is hydrogen, methyl or ethyl;  
 R 15  is hydrogen, C 1 -C 4 -alkyl, together with R 16  a —CH 2  group or a double bond,  
 R 16  is hydrogen, together with R 15  a —CH 2  group or a double bond;  
 comprising the following steps:  
 a) the reaction of compounds of general formula I  
                     
 in which  
 R 5  is hydroxy;  
 R 6a , R 6b , R 7a , R 7b , R 10 , R 11 , R 13 , R 15 , R 16  have the same meaning as in formula III, with at least 3 molar equivalents of an organic or inorganic hypochlorite as an oxidizing agent in the presence of catalytic amounts of a 2,2,6,6-tetramethyl-piperidine-N-oxide derivative at a pH of at least 8.0, in dichloromethane or in a two-phase dichloromethane-water mixture;  
 to form the compounds of formula II  
                     
 b) the isolation of compounds of formula II  
 c) subsequent elimination of water at pH<5, optionally in the presence of an acid.  
 
     
     
         6 . Process according to  claim 4  for the production of 3-oxo-17α-pregn-4-ene-21,17-carbolactones of formula IIa  
       
         
           
           
               
               
           
         
       
       in which 
 R 6a  is hydrogen or together with R 7a  a —CH 2  group;  
 R 6b  is hydrogen, together with R 7b  a —CH 2  group, or a double bond;  
 R 7a  is hydrogen, C 1 -C 4 -alkoxycarbonyl, or C 1 -C 4 -thioacyl;  
 R 7b  is hydrogen, or together with R 6b  a —CH 2  group,  
 R 9  is hydrogen, together with R 11  a double bond or together with R 11  an epoxy group -O-;  
 R 10  is hydrogen, or methyl;  
 R 11  is hydrogen, together with R 9  a double bond or together with R 9  an epoxy group -O-;  
 R 15  is hydrogen, together with R 16  a —CH 2  group or a double bond;  
 R 16  is hydrogen, together with R 15  a —CH 2  group or a double bond,  
 wherein the compounds of formula Ia  
                     
 are reacted.  
 
     
     
         7 . Process according to  claim 4  for the production of a compound of formula IIIb  
       
         
           
           
               
               
           
         
       
       whereby the compound of formula Ib  
       
         
           
           
               
               
           
         
       
       is used as a starting material.  
     
     
         8 . Process for the production of dichloromethane hemisolvate IV:  
       
         
           
           
               
               
           
         
       
       comprising the following steps: 
 a) the reaction of compounds of general formula Ib  
                     
 with at least 3 molar equivalents of an organic or inorganic hypochlorite as an oxidizing agent in the presence of catalytic amounts of a 2,2,6,6-tetramethyl-piperidine-N-oxide derivative at a pH of at least 8.0, in dichloromethane or in a two-phase dichloromethane-water mixture;  
 b) the isolation of compounds of formula II  
 
     
     
         9 . Process according to  claim 5 , wherein 1-5 mol % of the 2,2,6,6-tetramethylpiperidine-N-oxide derivative is used.  
     
     
         10 . Process according to  claim 5 , wherein 1-1.5 mol % of 2,2,6,6-tetramethylpiperidine-N-oxide is used.  
     
     
         11 . Process according to  claim 1 , wherein 3-6 molar equivalents of alkali hypochlorite are used.  
     
     
         12 . Process according to  claim 1 , wherein 3-4 molar equivalents of sodium hypochlorite are used.  
     
     
         13 . Process according to  claim 1 , wherein the pH of the reaction solution is between 8.5 and 10.0.  
     
     
         14 . Process according to  claim 1 , wherein the pH of the reaction solution is set with potassium bicarbonate.  
     
     
         15 . Process according to  claim 1 , wherein the reaction temperature is 0 to 15° C.  
     
     
         16 . Process according to  claim 1 , wherein after the oxidation reaction is completed, a reducing agent for quenching excess hypochlorite reagent is added to the reaction mixture.  
     
     
         17 . Process according to  claim 16 , wherein the reducing agent is added with the addition of a base or a basic buffer at a pH of more than 5.  
     
     
         18 . Process according to  claim 16 , wherein an aqueous alkali hydrogen sulfite solution is used as a reducing agent.  
     
     
         19 . Process according to  claim 16 , wherein as a reducing agent, sodium hydrogen sulfite or potassium hydrogen sulfite is used in the form of the aqueous solution of sodium disulfite or potassium disulfite.  
     
     
         20 . Process according to  claim 17 , wherein sodium phosphate (Na 3 PO 4 ) is used as a base or a basic buffer.  
     
     
         21 . 6β,7β; 15β, 16β-dimethylene-3-oxo-17α-pregnan-5β-ol-21,17-carbolactone-dichloromethane hemisolvate.  
     
     
         22 . Process for the production of drospirenone comprising reacting 6β,7β; 15β, 16β-dimethylene-3-oxo-17α-pregnan-5β-ol-21,17-carbolactone-dichloromethane hemisolvate with an acid.  
     
     
         23 . Process according to  claim 22 , wherein the acid is sulfuric acid, hydrochloric acid or para-toluenesulfonic acid.  
     
     
         24 . The compound of  claim 21  in isolated form.  
     
     
         25 . The process of  claim 22  wherein said hemisolvate was previously isolated.  
     
     
         26 . The process of  claim 1  further comprising isolating said compound of formula II.  
     
     
         27 . The process of  claim 2  further comprising isolating said compound of formula IIa.  
     
     
         28 . The process of  claim 3  further comprising isolating said compound of formula IIb.  
     
     
         29 . A process of  claim 1  wherein said number of molar equivalents is 3.0-3.5.  
     
     
         30 . A process of  claim 4  wherein said number of molar equivalents is 3.0-3.5.  
     
     
         31 . A process of  claim 5  wherein said number of molar equivalents is 3.0-3.5.