Method for the preparation of 21-hydroxy-6,19-oxidoprogesterone (21oh-6op)

Abstract

A method of preparing 21-hydroxy-6,19-oxidoprogesterone, or an acylated or phosphorlated version thereof.

1 . A method of preparing 21-hydroxy-6,19-oxidoprogesterone (1) or an acyl or phosphate derivative thereof. 
       
         
           
           
               
               
           
         
       
       the method comprising the steps
 a) providing 21-acetoxypregnenolone; 
 b) protecting the C-3 hydroxy group of 21-acetoxypregnenolone through formation of a labile ester; 
 c) obtaining the bromohydrin product thereof, by addition of a bromine and a hydroxy group onto the double bond of position of C5-C6 of the ester protected 21-acetoxy-pregnenolone; 
 d) performing an intramolecular cyclization with the C19 atom with the “Suarez-reagent” (diacetoxyiodobenzene) and iodine under irradiation, thus obtaining the 6,19 oxido-bridge within the scaffold; 
 e) performing a selective hydrolysis, followed by an oxidation, to obtain a bromo-ketone; 
 f) performing a hydrolysis of the bromoketone resulting from step e) to obtain 21-hydroxy-6,19-oxidoprogesterone (1); and optionally 
 g) reacting compound (I) with an acylating agent or phosphorylating agent. 
 
     
     
         2 . The method according to  claim 1 , wherein the 21-acetate derivative is obtained by acetylating 21-hydroxy-6,19-oxidoprogesterone (1) of step f). 
     
     
         3 . The method according to  claim 1 , wherein a C1-18 acyl derivative is obtained by esterifying 21-hydroxy-6,19-oxidoprogesterone with a C1-18 acid, anhydride, active ester or acyl chloride. 
     
     
         4 . The method according to  claim 1 , wherein a 21-propionate, 21-hemisuccinate, 21-phosphate, 21-oleate derivative is obtained by esterifying 21-hydroxy-6,19-oxidoprogesterone (1) of step f) with propionic acid, succinic acid, oleic acid or their anhydrides or active esters or acid chlorides. 
     
     
         5 . The method according to  claim 1 , wherein the 21-phosphate derivative is obtained by reacting oxidoprogesterone (1) of step (f) with a phosphorylating agent. 
     
     
         6 . The method according to any of the preceding claims wherein for step b) a formate ester is afforded. 
     
     
         7 . The method according to any of the preceding claims, wherein the intramolecular cyclisation step d) is performed in dichloromethane as solvent. 
     
     
         8 . The method according to any of the preceding claims, wherein the selective hydrolysis of step e) is performed with HCl in MeOH/dichloromethane as solvent. 
     
     
         9 . The method according to any of the preceding claims, wherein the oxidation in step e) is performed with pyridinium chlorochromate (PCC). 
     
     
         10 . The method according to any of the preceding claims, wherein the hydrolysis in step f) is performed with KOH in MeOH/dichloromethane as solvent. 
     
     
         11 . A method for preparing (6) 
       
         
           
           
               
               
           
         
       
       comprising the step of performing an intramolecular cyclisation between the 6-OH and the C 21  of the molecule (5) 
       
         
           
           
               
               
           
         
       
     
     
         12 . A method according to  claim 11 , wherein the intramolecular cyclisation is carried out by photoreaction with DIAB and I 2 . 
     
     
         13 . A method according to  claim 11  or  12 , wherein the intramolecular cyclisation is carried out in CH 2 Cl 2 .