Process for the preparation 2-substituted derivatives of estrone and estradiol

Abstract

The invention provides a process for the preparation of 2-substituted-derivatives of estrone and estradiol comprising i) the preparation of a compound of general formula (II) by reacting a compound of general formula (I) in one or more steps to a compound of general formula II wherein R1 is a C1-C10 alkyl, alkenyl or aryl group; —Cl, —Br, —I, —F; —CN; —OH; or a —OR2, —O(CO)R2 or —R2-OH group, wherein R2 is an alkyl or alkylene group having 1-6 C atoms; and the bonding between atoms 9 and 10 is a single or a double bond. ii) aromatization of the compound of general formula II to a compound of general formula III wherein R1 and R2 have the above defined meanings; and iii) optionally, reduction of the compound of general formula III to a compound of general formula IV wherein R1 and R2 have the above defined meanings. Furthermore the invention provides several novel compounds, which can be intermediates in the above process, and processes to prepare these novel compounds. The invention also provides 2-alkoxy-estrone, 2-alkoxy-estradiol or mixtures thereof essentially free from other estrogenic intermediates.

1 . Process for the preparation of 2-substituted-derivatives of estrone and estradiol comprising
 i) the preparation of a compound of general formula (II) by reacting a compound of general formula (I)   
       
         
           
           
               
               
           
         
       
       in one or more steps to a compound of general formula II 
       
         
           
           
               
               
           
         
       
       wherein R1 is a C1-C10 alkyl, alkenyl or aryl group; —Cl, —Br, —I, —F; —CN; —OH; or a —OR2, —O(CO)R2 or —R2-OH group, wherein R2 is an alkyl or alkylene group having 1-6 C atoms; and the bonding between atoms 9 and 10 is a single or a double bond.
 ii) aromatization of the compound of general formula II to a compound of general formula III 
 
       
         
           
           
               
               
           
         
       
       wherein R1 and R2 have the above defined meanings; and
 iii) optionally, reduction of the compound of general formula III to a compound of general formula IV 
 
       
         
           
           
               
               
           
         
       
       wherein R1 and R2 have the above defined meanings. 
     
     
         2 . Process according to  claim 1 , wherein in the compounds of general formulae II, III, and IV R1 is an —OR2 group, wherein R2 is an alkyl group having 1 to 6 carbon atoms. 
     
     
         3 . Process according to  claim 1  or  2 , wherein in the compound of general formula II the bonding between atoms 9 and 10 is a double bond. 
     
     
         4 . Process according to anyone of  claims 1 - 3 , wherein the aromatization in step ii) is carried with the help of lithium in ethylene diamine. 
     
     
         5 . Process according to anyone of  claims 1 - 4 , wherein the reduction in step iii) is carried out using NaBH 4  as a reduction agent. 
     
     
         6 . Compound of general formula II 
       
         
           
           
               
               
           
         
         wherein R1 is a C1-C10 alkyl, alkenyl or aryl group; —Cl, —Br, —I, —F; —CN; —OH; or a —OR2, —O(CO)R2 or —R2-OH group, wherein R2 is an alkyl or alkylene group having 1-6 C atoms; and the bonding between atoms 9 and 10 is a single or a double bond. 
       
     
     
         7 . Process for the preparation of a compound of general formula II, 
       
         
           
           
               
               
           
         
         wherein R1 is a C1-C10 alkyl, alkenyl or aryl group; —Cl, —Br, —I, —F; —CN; —OH; or a —OR2, —O(CO)R2 or —R2-OH group, wherein R2 is an alkyl or alkylene group having 1-6 C atoms; and the bonding between atoms 9 and 10 is a single or a double bond; 
         comprising the steps of 
         a) reacting a compound of formula I 
       
       
         
           
           
               
               
           
         
       
       with a compound of general formula V 
       
         
           
           
               
               
           
         
         wherein R1 and R2 have the above defined meanings; R3 and R4 independently are an alkyl group comprising 1 to 6 carbon atoms; and X is chosen from Cl or Br; 
         to prepare a compound of general formula (VI) 
       
       
         
           
           
               
               
           
         
         wherein R1, R2, R3 and R4, have the above defined meanings; 
         b) oxidizing the hydroxy group of the compound of general formula (VI) to generate a compound of general formula (VII) 
       
       
         
           
           
               
               
           
         
         wherein R1, R2, R3 and R4, have the above defined meanings; 
         c) ring-closing of the B-ring of the compound of general formula VII to prepare a compound with general formula VIII 
       
       
         
           
           
               
               
           
         
         wherein R1, R2, R3 and R4, have the above defined meanings; 
         d) reacting the compound of formula VIII in one or more steps to a compound of general formula II. 
       
     
     
         8 . Process according to  claim 7 , wherein the reaction of step d) comprises
 d1) hydrolysis of a compound of general formula VIII, wherein the bonding between atoms 9 and 10 is a double bond, to obtain a compound of general formula IX,   
       
         
           
           
               
               
           
         
         wherein R1 is a C1-C10 alkyl, alkenyl or aryl group; —Cl, —Br, —I, —F; —CN; —OH; or a —OR2, —O(CO)R2 or —R2-OH group, wherein R2 is an alkyl or alkylene group having 1-6 C atoms; 
         d2) ring-closure of the A-ring to obtain a compound of general formula II, wherein the bonding between atoms 9 and 10 is a double bond, from the compound of general formula IX. 
       
     
     
         9 . Process according to  claim 7 , wherein the reaction of step d) comprises
 d3) hydrogenation of the double bond between atoms 9 and 10 of the compound of general formula VIII to obtain a compound of general formula X;   
       
         
           
           
               
               
           
         
         d4) hydrolysis of the compound of general formula X to obtain a compound of general formula XI; 
       
       
         
           
           
               
               
           
         
         d5) ring-closure of the A-ring in the compound of general formula XI, to obtain a compound of general formula II, wherein the bonding between atoms 9 and 10 is a single bond. 
       
     
     
         10 . Compound of general formula V 
       
         
           
           
               
               
           
         
       
       wherein R1 is a C1-C10 alkyl, alkenyl or aryl group; —Cl, —Br, —I, —F; —CN; —OH; or a —OR2, —O(CO)R2 or —R2-OH group, wherein R2 is an alkyl or alkylene group comprising 1 to 6 carbon atoms; R3 and R4 independently are an alkyl group comprising 1 to 6 carbon atoms; and X is chosen from Cl or Br; 
     
     
         11 . Compound of general formula (VI) 
       
         
           
           
               
               
           
         
       
       wherein R1 is a C1-C10 alkyl, alkenyl or aryl group; —Cl, —Br, —I, —F; —CN; —OH; or a —OR2, —O(CO)R2 or —R2-OH group, wherein R2 is an alkyl or alkylene group comprising 1 to 6 carbon atoms; R3 and R4 independently are an alkyl group comprising 1 to 6 carbon atoms. 
     
     
         12 . Compound of general formula (VII) 
       
         
           
           
               
               
           
         
       
       wherein R1 is a C1-C10 alkyl, alkenyl or aryl group; —Cl, —Br, —I, —F; —CN; —OH; or a —OR2, —O(CO)R2 or —R2-OH group, wherein R2 is an alkyl or alkylene group comprising 1 to 6 carbon atoms; R3 and R4 independently are an alkyl group comprising 1 to 6 carbon atoms. 
     
     
         13 . Compound of general formula VIII 
       
         
           
           
               
               
           
         
       
       wherein R1 is a C1-C10 alkyl, alkenyl or aryl group; —Cl, —Br, —I, —F; —CN; —OH; or a —OR2, —O(CO)R2 or —R2-OH group, wherein R2 is an alkyl or alkylene group comprising 1 to 6 carbon atoms; R3 and R4 independently are an alkyl group comprising 1 to 6 carbon atoms. 
     
     
         14 . Compound of general formula IX, 
       
         
           
           
               
               
           
         
       
       wherein R1 is a C1-C10 alkyl, alkenyl or aryl group; —Cl, —Br, —I, —F; —CN; —OH; or a —OR2, —O(CO)R2 or —R2-OH group, wherein R2 is an alkyl or alkylene group comprising 1 to 6 carbon atoms. 
     
     
         15 . Compound of general formula X, 
       
         
           
           
               
               
           
         
       
       wherein R1 is a C1-C10 alkyl, alkenyl or aryl group; —Cl, —Br, —I, —F; —CN; —OH; or a —OR2, —O(CO)R2 or —R2-OH group, wherein R2 is an alkyl or alkylene group comprising 1 to 6 carbon atoms; R3 and R4 independently are an alkyl group comprising 1 to 6 carbon atoms. 
     
     
         16 . Compound of general formula XI, 
       
         
           
           
               
               
           
         
       
       wherein R1 is a C1-C10 alkyl, alkenyl or aryl group; —Cl, —Br, —I, —F; —CN; —OH; or a —OR2, —O(CO)R2 or —R2-OH group, wherein R2 is an alkyl or alkylene group comprising 1 to 6 carbon atoms. 
     
     
         17 . 2-alkoxy-estrone, 2-alkoxy-estradiol or mixtures thereof essentially free from estrogenic intermediates.