Pharmaceutically active morpholinol

Abstract

Disclosed is the compound (+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol and pharmaceutically acceptable salts and solvates thereof, methods for preparing them, pharmaceutical compositions comprising them, and processes for their preparation; also disclosed is a method of treating depression, attention deficit hyperactivity disorder (ADHD), obesity, migraine, sexual dysfunction, Parkinson's disease, Alzheimer's disease, or addiction to cocaine or nicotine-containing (especially tobacco) products using such compound, salts, solvates or compositions.

1 . A process for preparing optically pure (+)-(2S, 3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol or a pharmaceutically acceptable salt or solvate thereof which comprises 
 treating racemic 2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol with a chiral acid under suitable reaction conditions and in a suitable solvent to form a mixture of diastereomeric salts;    isolating from the mixture of the diastereomeric salts a chiral salt of (+)-(2S, 3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol; and    contacting the chiral salt of (+)-(2S, 3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol with a base.    
     
     
         2 . A process as claimed in  claim 1 , wherein the chiral acid is di-p-toluyl-L-tartaric acid.  
     
     
         3 . A process as claimed in  claim 1 , wherein the solvent is selected from ethanol, IMS and acetonitrile.  
     
     
         4 . A process as claimed in  claim 1 , wherein the solvent is selected from the group consisting of ethanol, water, and mixtures thereof.  
     
     
         5 . A process as claimed in  claim 1 , wherein the base is selected from sodium hydrogencarbonate, potassium carbonate, aqueous ammonia, and ammonium hydroxide.  
     
     
         6 . A process as claimed in  claim 2 , wherein the di-p-toluyl-L-tartaric acid is used in about 1.4 to about 2.0 equivalents relative to the racemic 2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol.  
     
     
         7 . A process as claimed in  claim 6 , wherein about 1.5 to about 2.0 equivalents of di-p-toluyl-L-tartaric acid are used.  
     
     
         8 . A process as claimed in  claim 2 , wherein the racemic 2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol solution is added as a solution to the di-p-toluyl-L-tartaric acid as a solution.  
     
     
         9 . The process as claimed in  claim 1 , wherein the solvent is ethyl acetate.  
     
     
         10 . A process for preparing optically pure (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol or a pharmaceutically acceptable salt or solvate thereof which comprises: 
 brominating 3-chloropropiophenone to form an intermediate;    contacting the intermediate with 2-amino-2-methyl-1-propanol under suitable reaction conditions for the formation of racemic 2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol;    contacting the racemic 2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol with a chiral acid under suitable reaction conditions to form a mixture of diastereomeric salts;    isolating from the mixture of the diastereomeric salts a chiral salt of (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; and    contacting the chiral salt of (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol with a base.    
     
     
         11 . The process of  claim 10 , wherein the formation of diastereomeric salts and/or isolation of the chiral salt of (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol gives a mother liquor.  
     
     
         12 . The process of  claim 10 , wherein the chiral acid is an optically pure derivative of tartaric acid.  
     
     
         13 . The process of  claim 10 , wherein the base is selected from the group consisting of potassium carbonate, potassium hydroxide, sodium hydroxide, and ammonium hydroxide.  
     
     
         14 . The process of  claim 10 , wherein the chiral acid is di-p-toluoyl-L-tartaric acid.  
     
     
         15 . The process of  claim 10 , wherein the solvent is ethyl acetate.