Processes for the preparation of s1p1 receptor modulators and crystalline forms thereof

Abstract

The present invention relates to salts, processes, and process intermediates useful in the preparation of (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid of Formula (Ia), salts, and crystalline forms thereof. The compound (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid has been identified as an S1P1 receptor modulator that is useful in the treatment of S1P1 receptor-associated disorders, for example, diseases and disorders mediated by lymphocytes, transplant rejection, autoimmune diseases and disorders, inflammatory diseases and disorders (e.g., acute and chronic inflammatory conditions), cancer, and conditions characterized by an underlying defect in vascular integrity or that are associated with angiogenesis such as may be pathologic (e.g., as may occur in inflammation, tumor development, and atherosclerosis).

1 - 14 . (canceled) 
     
     
         15 . A process for preparing an L-lysine salt of (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid of Formula (Ia): 
       
         
           
           
               
               
           
         
         comprising the steps of: 
         a) hydrolyzing said compound of Formula (IIn): 
       
       
         
           
           
               
               
           
         
         wherein R 6  is C 1 -C 4  alkyl; 
       
       in the presence of a hydrolyzing-step base and a hydrolyzing-step solvent to form said (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid; and
 b) contacting said (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid with L-lysine or a salt thereof, in the presence of a contacting-step solvent and H 2 O to form said L-lysine salt of (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid. 
 
     
     
         16 . A process for preparing an L-lysine salt of (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid of Formula (Ia): 
       
         
           
           
               
               
           
         
         comprising the step of: 
         contacting the (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid with L-lysine or a salt thereof, in the presence of a contacting-step solvent and H 2 O to form said L-lysine salt of (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid. 
       
     
     
         17 . The process according to  claim 16 , wherein said contacting-step solvent comprises acetonitrile, tetrahydrofuran, acetone, or ethyl acetate. 
     
     
         18 . The process according to  claim 16 , wherein said contacting-step solvent comprises ethanol or isopropanol. 
     
     
         19 . The process according to  claim 16 , wherein the molar ratio between said (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid and L-lysine is about 1.0:1.0 to about 1.0:1.2. 
     
     
         20 . The process according to  claim 16 , said process further comprising the step of isolating said L-lysine salt of (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid. 
     
     
         21 . The process according to  claim 20 , wherein after said isolating, said L-lysine salt of (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid has a purity of about 97% or greater, and an enantiomeric excess of about 97% or greater. 
     
     
         22 . A process for preparing (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid of Formula (Ia): 
       
         
           
           
               
               
           
         
         comprising the step of: 
       
       hydrolyzing a compound of Formula (IIn): 
       
         
           
           
               
               
           
         
         wherein R 6  is C 1 -C 4  alkyl; 
       
       in the presence of a hydrolyzing-step base and a hydrolyzing-step solvent to form said (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid. 
     
     
         23 . The process according to  claim 22 , wherein R 6  is CH 2 CH 3 . 
     
     
         24 . The process according to  claim 22 , wherein said hydrolyzing-step base comprises sodium hydroxide. 
     
     
         25 . The process according to  claim 22 , wherein said hydrolyzing-step solvent comprises dioxane, methanol, and water. 
     
     
         26 . The process according to  claim 22 , wherein said hydrolyzing further comprises the step of isolating said (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid. 
     
     
         27 . The process according to  claim 26 , wherein after said isolating, said (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid has an enantiomeric excess of about 97% or greater. 
     
     
         28 - 40 . (canceled) 
     
     
         41 . A process for preparing a composition comprising admixing a salt selected from:
 (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid L-lysine salt;   (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid sodium salt;   (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid sodium salt hydrate;   (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid ethylenediamine salt hydrate;   (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid 2-amino-2-hydroxymethyl-propane-1,3-diol salt;   (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid L-arginine salt;   (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid zinc salt;   (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid calcium salt;   (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid N-methylglucamine salt;   (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid potassium salt; and   (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid magnesium salt;   
       and a pharmaceutically acceptable carrier. 
     
     
         42 - 56 . (canceled)