Process for the preparation of (S,S)-cis-2-benzhydryl-3-benzylaminoquinuclidine

Abstract

A process for preparing (S,S)-cis-2-benzhydryl-3-benzylaminoquinuclidine. The process includes the steps of contacting a compound containing a mixture of R- and S-isomers and having the formula with an effective amount of a chiral organic acid in the presence of an organic solvent and an effective amount of an organic carboxylic acid for converting the R-isomer into an acid salt of the S isomer, wherein the organic solvent is capable of solubilizing the compound containing the mixture of R- and S-isomers, while precipitating the acid salt and the organic carboxylic acid is different from the chiral organic acid; neutralizing the acid salt with a base to provide an S-isomer-of a chiral ketone of the formula reacting the chiral ketone with an organic amine in the presence of a Lewis acid to provide the corresponding imine and reducing the imine.

1 - 30 . (canceled)  
     
     
         31 . A salt of 2(S)-benzhydryl-3-quinuclidinone, said salt being substantially enantiomerically pure.  
     
     
         32 . The salt of claim  30 , which is the tartrate salt.  
     
     
         33 . A substantially enantiomerically pure 2(S)-benzhydryl-3-quinuclidinone.  
     
     
         34 . A substantially enantiomerically pure irnine of 2(S)-benzhydryl-3-quinuclidinone.  
     
     
         35 . A process for preparing a substantially enantiomerically pure heat of 2(S)benzhyryl-3-quinuclidinone comprising the steps of: 
 contacting a compound containing a mixture of R- and S-isomers and having the formula                          with an effective amount of a chiral organic acid in the presence of an organic solvent and an effective amount of an organic carboxylic acid for converting said R-isomer into an acid salt of said S isomer, said organic solvent being capable of solubilizing said compound containing said mixture of R- and S-isomers, while precipitating said acid salt and said organic carboxylic acid being different from said chiral organic acid;    neutralzing said acid salt with a base to provide an S-isomer of a chiral ketone of the formula                          
     
     
         36 . The process of  claim 35 , wherein the compound is present as a racemic mixture.  
     
     
         37 . The process of  claim 35 , wherein said acid salt is a tartrate salt of (2S)-benzhydryl-3-quinuclidinone.  
     
     
         38 . The process of  claim 35 , wherein said chiral organic acid is L-tartaric acid.  
     
     
         39 . The process of  claim 35 , wherein said effective amount of said chiral organic acid employed is at least one equilivant or more.  
     
     
         40 . The process of  claim 35 , wherein said organic solvent is an alcohol.  
     
     
         41 . The process of  claim 35 , wherein said alcohol is ethanol.  
     
     
         42 . The process of  claim 40 , wherein said alcohol is a denatured alcohol.  
     
     
         43 . The process of  claim 35 , wherein said organic carboxylic acid is acetic acid, propionic acid or butyric acid.  
     
     
         44 . The process of  claim 43 , wherein said organic carboxylic acid is acetic acid.  
     
     
         45 . The process of  claim 35 , wherein said effective amount of said organic carboxylic acid employed is at least one equivalent, relative to said compound.  
     
     
         46 . The process of  claim 35 , wherein said base is sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.  
     
     
         47 . The process of  claim 35 , wherein said base is added with cooling to maintain a temperature below 25° C. until reaching a pH of about 9.  
     
     
         48 . The process of  claim 35 , wherein said neutralizing is performed in the presence of a biphasic solvent mixture.  
     
     
         49 . The process of  claim 48 , wherein said biphasic solvent mixture comprises a second organic solvent and water.  
     
     
         50 . The process of  claim 49 , wherein said second organic solvent is toluene, ethyl acetate, or methyl t-butyl ether.  
     
     
         51 . The process of  claim 35 , wherein said acid salt is produced in a yield greater than 50%.  
     
     
         52 . The process of  claim 51 , wherein said yield is from 85 to 90%.