Process for the preparation of 7alpha-alkylated 19-norsteroids

Abstract

Processes useful in the preparation of pharmaceutical compounds such as fulvestrant and processes for the preparation of fulvestrant.

1 - 8 . (canceled) 
   
   
       9 . A process for preparing the compound of formula (II), 
     
       
         
         
             
             
         
       
     
     comprising:
 a) combining a 19-nor-androsta-4,6-diene-3-one of formula (III) 
 
     
       
         
         
             
             
         
       
     
     with an etheral solvent, to obtain a solution;
 b) cooling the solution to a temperature of about −60° C. to about 30° C.; 
 c) adding to the solution of step a), in a drop-wise manner, a solution of the compound of formula (IV) 
 
     
       
         
         
             
             
         
       
     
     in an etheral solvent to obtain a reaction mixture;
 d) quenching the reaction mixture; and 
 e) recovering the compound of formula (II); 
 wherein
 n is an integer ranging from 3 to 14; 
 X is either O or S; 
 R 1  is a C 1-10  haloalkyl or a hydroxy protecting group; 
 R 2  is either hydrogen, C 1-6  alkyl, hydroxyl, protected hydroxy, or halo; 
 R 3  is either hydrogen, C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl; 
 R 4  is a C 1-6  acyloxy; 
 R 5  is C 1-6  alkyl; and 
 R 6  is either hydrogen, C 1-6  alkyl, hydroxyl, protected hydroxy, or halo; and 
 z is a metal halide of the formula R 7 M, wherein
 M is a metal atom; and 
 R 7  is a halogen atom. 
 
 
 
   
   
       10 . The process of  claim 9 , wherein n is 9, X is O, R 1  is tertbutyl-dimethylsilyl (TBDMS), R 2 , R 3  and R 6  are hydrogens, R 4  is acetyloxy and R 5  is methyl. 
   
   
       11 . The process of  claim 9 , wherein n is 5, X is O, R 1  is TBDMS, R 3  and R 6  are hydrogens, R 4  is acetyloxy and R 5  is methyl. 
   
   
       12 . The process of  claim 9 , wherein n is 9, X is S, R 1  is —(CH 2 ) 3 CF 2 CF 3 , R 2 , R 3  and R 6  are hydrogens, R 4  is acetyloxy and R 5  is methyl. 
   
   
       13 . The process of  claim 9 , wherein M is a metal atom selected from the group consisting of magnesium, zinc, aluminum, copper, copper-lithium and titanium. 
   
   
       14 . The process of  claim 13 , wherein M is magnesium. 
   
   
       15 . The process of  claim 9 , wherein R 7  is selected from the group consisting of Cl, Br and I. 
   
   
       16 . The process of  claim 15 , wherein R 7  is Br. 
   
   
       17 . The process of  claim 14 , wherein a copper catalyst is a combined in step a) with the 19-nor-androsta-4,6-diene-3-one of formula (III) and the etheral solvent. 
   
   
       18 . The process of  claim 17 , wherein said copper catalyst is in the form of Cu(I)Y, wherein Y is Cl, Br or I. 
   
   
       19 . The process of  claim 18 , wherein said copper catalyst is Cu(I)Cl. 
   
   
       20 . The process of  claim 9 , wherein the compound of formula (II) obtained in step e) has a ratio of 7α- to 7β-epimer of about 2.5:1 to about 12.1:1. 
   
   
       21 . The process of  claim 20 , wherein the compound of formula (II) obtained in step e) has a ratio of 7α- to 7β-epimer of about 12.1:1. 
   
   
       22 . The process of  claim 9 , wherein the etheral solvent in step a) is selected from the group consisting of: diethyl ether, THF and glyme. 
   
   
       23 . The process of  claim 22 , wherein said etheral solvent is THF. 
   
   
       24 . The process of  claim 9 , wherein the solution of step b) is cooled to a temperature of about −20° C. to about −10° C. 
   
   
       25 . The process of  claim 9 , wherein the reaction mixture in step d) is quenched by one of the reagents selected from the group consisting of: NH 4 Cl, HCl, water, acetic acid and a mixture of NH 4 Cl with NH 4 OH. 
   
   
       26 . The process of  claim 25 , wherein the reaction mixture is quenched with acetic acid. 
   
   
       27 . The process of  claim 9 , further comprising converting the compound of formula (II) obtained in step e) to fulvestrant. 
   
   
       28 - 62 . (canceled)