INHIBITORS OF RORgamma

Abstract

The present disclosure relates to processes for the production of salts and crystalline forms of a compound having the formula.

1 . A method of removing methyl bromide from a composition comprising methyl bromide and crystalline form D bis-hydrogen bromide salt of a compound having the following structural: 
       
         
           
           
               
               
           
         
         comprising: 
         i) slurrying the composition in a mixture of isopropyl acetate/water or a mixture of heptane/water; and 
         ii) separating the crystalline form D bis-hydrogen bromide salt from the mixture of isopropyl acetate/water or the mixture of heptane/water. 
       
     
     
         2 . The method of  claim 1 , wherein the composition is slurried in a mixture of isopropyl acetate/water. 
     
     
         3 . The method of  claim 1 , wherein the composition is slurried in a mixture of isopropyl acetate comprising 0.25% to 2.5% v/v of water. 
     
     
         4 . The method of  claim 1 , wherein the composition is slurried in a mixture of isopropyl acetate comprising 0.5% to 2.0% v/v of water. 
     
     
         5 . The method of  claim 1 , wherein the composition is slurried in a mixture of isopropyl acetate comprising 0.9% to 1.1% v/v of water. 
     
     
         6 . The method of  claim 1 , wherein the composition comprises greater than 45 ppm of methyl bromide prior to slurrying. 
     
     
         7 . The method of  claim 1 , wherein the crystalline form D bis-hydrogen bromide salt after separation comprises less than 40 ppm of methyl bromide. 
     
     
         8 . The method of  claim 1 , wherein the crystalline form D bis-hydrogen bromide salt after separation comprises an amount of methyl bromide that is below the level of detection. 
     
     
         9 . The method of  claim 1 , wherein the crystalline form D bis-hydrogen bromide salt is separated by filtration. 
     
     
         10 - 14 . (canceled) 
     
     
         15 . A method of forming a compound having the Formula: 
       
         
           
           
               
               
           
         
         comprising the steps of 
         i) reductively aminating an aldehyde compound represented by the following structural formula: 
       
       
         
           
           
               
               
           
         
       
       with an amine compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       wherein the reductive amination is carried out in the presence of an imine reducing agent;
 ii) quenching the reductive amination mixture with acid; 
 iii) neutralizing the resulting solution with base, thereby precipitating the free base form of the compound; and 
 iv) isolating the precipitated free-base form of the compound. 
 
     
     
         16 . The method of  claim 15 , further comprising carrying out the reductive amination in ethanol as the solvent. 
     
     
         17 . The method of  claim 15 , wherein the acid is hydrochloric acid and the base is sodium hydroxide. 
     
     
         18 . The method of  claim 15 , wherein the imine reducing agent is sodium triacetoxyborohydride. 
     
     
         19 . The method of  claim 15 , wherein the solution is neutralized in step iii) to pH 5 to 7. 
     
     
         20 . The method of  claim 15 , wherein the amine compound is formed in situ from treating an acid salt form of the amine with a tertiary amine base. 
     
     
         21 . The method of  claim 15 , wherein the amine is formed in situ from treating a di-hydrochloric acid salt form of the amine with diisopropylethylamine. 
     
     
         22 . The method of  claim 15 , further comprising v) adding to the isolated free base, a sufficient amount of hydrobromic acid to form a bis-hydrogen bromide salt having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The method of  claim 22 , further comprising the addition of isopropanol, MTBE, and acetic acid. 
     
     
         24 . The method of  claim 22 , wherein said sufficient amount of hydrobromic acid comprises 2 to 3 equivalents of 40% or 48% hydrobromic acid.