Processes for preparing (r)-2-methylpyrrolidine and (s)-2-methylpyrrolidine and tartrate salts thereof

Abstract

The present invention provides a short, safe, inexpensive, commercially scalable process for preparing (R)- or (S)-2-methylpyrrolidine from 2-methylpyrroline, which does not require the isolation of synthetic intermediates.

1 . A process for preparing (R)-2-methylpyrrolidine L-tartrate, comprising the steps of:
 (a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;   (b) optionally removing the hydrogenation catalyst from the mixture;   (c) dissolving L-tartaric acid in the mixture to form a solution;   (d) crystallizing (R)-2-methylpyrrolidine L-tartrate from the solution; and   (e) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate.   
   
   
       2 . The process of  claim 1 , wherein the hydrogenation catalyst is a platinum catalyst. 
   
   
       3 . The process of  claim 2 , wherein the platinum catalyst is 5% Pt—C. 
   
   
       4 . The process of  claim 2 , wherein the platinum catalyst is platinum (IV) oxide. 
   
   
       5 . The process of any of  claims 1 - 4 , wherein the alcohol solvent is a mixture of ethanol and methanol. 
   
   
       6 . The process of  claim 5 , wherein the alcohol solvent is a mixture of ethanol and methanol at a ratio of about 2:1 to about 3:1 (v/v). 
   
   
       7 . The process of any of  claims 1 - 6 , wherein step (a) is performed at ambient temperature. 
   
   
       8 . The process of any of  claims 2 - 4 , wherein the platinum catalyst is removed in step (b) by filtration. 
   
   
       9 . The process of any of  claims 1 - 8 , wherein the isolated (R)-2-methylpyrrolidine L-tartrate has an optical purity of at least 50% ee. 
   
   
       10 . The process of any of  claims 1 - 9 , further comprising the steps of:
 (f) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate;   (g) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate; and   (h) optionally repeating steps (f) and (g).   
   
   
       11 . The process of  claim 10 , further comprising the step of reacting the isolated recrystallized (R)-2-methylpyrrolidine L-tartrate with a base to provide (R)-2-methylpyrrolidine. 
   
   
       12 . The process of any of  claims 1 - 9 , further comprising the step of converting the prepared (R)-2-methylpyrrolidine L-tartrate into an H 3  receptor ligand. 
   
   
       13 . The process of  claim 10  or  11 , further comprising the step of converting the prepared (R)-2-methylpyrrolidine L-tartrate into an H 3  receptor ligand. 
   
   
       14 . The process of  claim 12  or  13 , wherein the H 3  receptor ligand is 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one: 
     
       
         
         
             
             
         
       
     
   
   
       15 . A process for preparing 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one: 
     
       
         
         
             
             
         
       
     
     comprising the steps of:
 (1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; 
 (1b) optionally removing the hydrogenation catalyst from the mixture; 
 (1c) dissolving L-tartaric acid in the mixture to form a solution; 
 (1d) crystallizing (R)-2-methylpyrrolidine L-tartrate from the solution; 
 (1e) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate; and 
 (2) reacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2-methylpyrrolidine free base; and 
 (3) reacting the (R)-2-methylpyrrolidine with 6-[4-(3-halo-propoxy)-phenyl]-2H-pyridazin-3-one for a time and under conditions sufficient to form (R)-6-{4-[3-(2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one. 
 
   
   
       16 . The process of  claim 15 , wherein the 6-[4-(3-halo-propoxy)-phenyl]-2H-pyridazin-3-one is prepared by the steps of:
 (a) contacting 1-(4-hydroxy-phenyl)-ethanone with 1,3-dihalopropane, for a time and under conditions sufficient to form 1-[4-(3-halo-propoxy)-phenyl]-ethanone; and   (b) contacting the 1-[4-(3-halo-propoxy)-phenyl]-ethanone with glyoxalic acid for a time and under conditions sufficient to produce 6-[4-(3-halo-propoxy)-phenyl]-2H-pyridazin-3-one.   
   
   
       17 . The process of  claim 15 , further comprising the steps of:
 (f) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate;   (g) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate; and   (h) optionally repeating steps (f) and (g).   
   
   
       18 . A process for preparing (S)-2-methylpyrrolidine D-tartrate, comprising the steps of:
 (a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;   (b) optionally removing the hydrogenation catalyst from the mixture;   (c) dissolving D-tartaric acid in the mixture to form a solution;   (d) crystallizing (S)-2-methylpyrrolidine D-tartrate from the solution; and   (e) isolating the crystalline (S)-2-methylpyrrolidine D-tartrate.   
   
   
       19 . The process of  claim 18 , wherein the hydrogenation catalyst is a platinum catalyst. 
   
   
       20 . The process of  claim 19 , wherein the platinum catalyst is 5% Pt—C. 
   
   
       21 . The process of  claim 20 , wherein the platinum catalyst is platinum (IV) oxide. 
   
   
       22 . The process of any of  claims 18 - 21 , wherein the alcohol solvent is a mixture of ethanol and methanol.