Methods for producing viloxazine salts and novel polymorphs thereof

Abstract

Provided here are methods of manufacture of viloxazine and its various salts, as well as viloxazine-related compounds, such as novel intermediate reaction products and polymorphs thereof. In particular, the methods provide a substantially pure API of viloxazine HCl while avoiding undesirable impurities. The methods further provide for separating, identifying, and characterizing novel polymorphs of viloxazine. Further provided are methods for synthesis and identification and characterization of novel intermediates of viloxazine, as well as for some important metabolites and precursors of metabolites of viloxazine.

1 - 4 . (canceled) 
     
     
         5 . A method of manufacturing a 2-substituted morpholine comprising providing a diol compound according to the following formula: 
       
         
           
           
               
               
           
         
         wherein R b  is a hydrogen or nitrogen-protecting group, and R c  is a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkoxy group; and reacting said diol compound in a solvent system with a base or a cyclization agent to produce a 2-substituted morpholine having the following formula: 
       
       
         
           
           
               
               
           
         
       
     
     
         6 . The method according to  claim 5 , wherein a phase transfer catalyst is used in the reacting step. 
     
     
         7 . The method according to  claim 5 , wherein the solvent system is a liquid/liquid biphasic system or a monophasic organic system. 
     
     
         8 . The method according to  claim 5 , wherein the base is a solid. 
     
     
         9 . A compound according to the following formula: 
       
         
           
           
               
               
           
         
         wherein R a  is a substituted or unsubstituted aryloxy group or a substituted or unsubstituted alkoxy group, and R b  is a hydrogen or nitrogen-protecting group. 
       
     
     
         10 . The compound according to  claim 9 , wherein R a  is ortho-ethoxy. 
     
     
         11 . The compound according to  claim 9 , wherein said nitrogen-protecting group is a benzyl group. 
     
     
         12 - 15 . (canceled) 
     
     
         16 . The method according to  claim 7 , wherein the monophasic solvent system comprises toluene. 
     
     
         17 . The method according to  claim 8 , wherein said base is sodium hydroxide. 
     
     
         18 - 30 . (canceled) 
     
     
         31 . A composition comprising a compound of selected from Compounds A-E: 
       
         
           
           
               
               
           
         
       
       or salts thereof. 
     
     
         32 . (canceled)