Treprostinil production

Abstract

The present invention is directed to a novel method for preparing a synthetic intermediates for treprostinil. Also described are methods of preparing treprostinil comprising utilizing novel intermediates described herein as well as novel intermediates useful for synthesis prostacyclin derivatives, such as treprostinil.

What is claimed is: 
     
         1 . A process of preparing treprostinil or a pharmaceutically acceptable salt thereof, of the formula: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof, which comprises:
 (a) derivatizing m-hydroxybenzaldehyde with an allyl halide, to form an oxyalkene-substituted benzaldehyde of formula: 
 
       
         
           
           
               
               
           
         
         (b) subjecting the substituted oxyalkene-substituted benzaldehyde to Claisen rearrangement to form the m-hydroxy-substituted benzaldehyde of formula: 
       
       
         
           
           
               
               
           
         
         (c) protecting the m-hydroxy-substituted benzaldehyde with a p-methoxybenzyl, to form a protected benzaldehyde of formula: 
       
       
         
           
           
               
               
           
         
       
       wherein R is p-methoxybenzyl
 (d) reacting the protected benzaldehyde with a 5-oxy-substituted decan-1,2-yne of formula: 
 
       
         
           
           
               
               
           
         
       
       wherein P 1  is an alcohol protecting group, to yield the compound of formula: 
       
         
           
           
               
               
           
         
       
       wherein R and P 1  are defined above;
 (e) oxidizing the resulting compound to a ketone compound of: 
 
       
         
           
           
               
               
           
         
       
       wherein R and P 1  are defined above;
 (f) chirally reducing the ketone compound to a chiral alcohol compound of formula: 
 
       
         
           
           
               
               
           
         
       
       wherein R and P 1  are defined above;
 (g) protecting the chiral alcohol compound to yield a compound of formula: 
 
       
         
           
           
               
               
           
         
       
       wherein R is defined above, and P 1 , for each occurrence is independently an alcohol protecting group;
 (h) intra-molecularly cyclizing the resulting compound to obtain a tricyclic enone compound of formula: 
 
       
         
           
           
               
               
           
         
       
       wherein R is defined above, and P 1 , for each occurrence is independently an alcohol protecting group;
 (i) hydrogenating the tricyclic enone to form a tricyclic hydroxyl compound of formula: 
 
       
         
           
           
               
               
           
         
       
       and
 (j) converting the preceding compound into treprostinil or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The process of  claim 1  including the additional, final step of converting the treprostinil so formed to its sodium salt.