Salts of treprostinil

Abstract

Provided are novel treprostinil salts as well as methods for making treprostinil salts.

What is claimed is: 
     
         1 . A method of synthesizing a treprostinil salt comprising:
 a) alkylating benzindene triol with an alkylating reagent to form an intermediate selected from a nitrile intermediate and an ester intermediate;   b) hydrolyzing the intermediate with a base or a base salt to form a treprostinil salt; and   c) isolating and crystallizing the treprostinil salt, wherein a solvent in each of steps a), b) and c) is the same.   
     
     
         2 . The method of  claim 1 , wherein the alkylating agent is 
       
         
           
           
               
               
           
         
       
       wherein X is Cl, Br or I and R is CN or COOR′, wherein R′ is an alkyl group or a substituted or unsubstituted benzyl group. 
     
     
         3 . The method of  claim 2 , wherein the intermediate is a nitrile intermediate and R is CN. 
     
     
         4 . The method of  claim 2 , wherein the intermediate is an ester intermediate having the following formula: 
       
         
           
           
               
               
           
         
       
       and R is COOR′. 
     
     
         5 . The method of  claim 4 , wherein R′ is a (C 1 -C 6 )alkyl. 
     
     
         6 . The method of  claim 4 , wherein R′ is unsubstituted benzyl. 
     
     
         7 . The method of  claim 4 , wherein R′ is benzyl substituted at one or more meta, ortho or para positions with one or more substituents selected from the group consisting of —NO 2 , —CN, halogen, (C1-C3)alkyl, halo(C1-C3)alkyl, (C1-C3)alkoxy and halo(C1-C3)alkoxy. 
     
     
         8 . The method of  claim 1 , wherein said hydrolyzing is performed with a hydroxide selected from the group consisting of ammonia hydroxide and a metal hydroxide. 
     
     
         9 . The method of  claim 8 , wherein said hydrolyzing is performed with a hydroxide of a Group IA or Group IIA metal. 
     
     
         10 . The method of  claim 9 , wherein said hydrolyzing is performed with a hydroxide of K, Ca, Mg, Ba, Cs, Li or Na. 
     
     
         11 . The method of  claim 1 , wherein said hydrolyzing is performed with a carbonate basic salt. 
     
     
         12 . The method of  claim 11 , wherein the carbonate basic salt is lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate or ammonium carbonate. 
     
     
         13 . The method of  claim 1 , wherein said alkylating is performed in the presence of an alkylating catalyst. 
     
     
         14 . The method of  claim 13 , wherein the alkylating catalyst is tetrabutyl ammonium bromide, potassium iodide or sodium iodide. 
     
     
         15 . The method of  claim 1 , wherein the solvent in each of steps a), b) and c) is selected from ethanol, isopropyl alcohol, methanol, acetone, ethyl acetate, hexanes, heptanes, isopropyl acetate or a combination thereof.