Synthesis of 3-amino-3-aryl propanoates

Abstract

A process for the synthesis of a compound of the formula wherein R 1 is aryl, heteroaryl, substituted aryl or substituted heteroaryl and R 2 is hydrogen, alkyl or aralkyl, or salt thereof.

We claim:  
     
         1 . A process for preparing a compound of the formula I  
                   wherein R 1  is aryl, heteroaryl, substituted aryl or substituted heteroaryl and R 2  is hydrogen, alkyl or aralkyl, or a salt thereof,    comprising reacting a compound of the formula II  
                 
   wherein R 1  is as described above and R 2′  is alkyl or aralkyl, with a compound of the formula III  
                 
   wherein R 5  is hydrogen or alkoxy,    under conditions of reduced pressure, such that the reaction solution boils at temperatures of between about 40° and about 65°C., in an inert solvent, which solvent under reduced pressure is capable of azeotropic removal of water, to form the compound of formula IV,  
                 
   reacting the compound of formula IV with hydrogen gas in the presence of a palladium catalyst to form the compound of formula V  
                 
   and reacting the compound of formula V to form the compound of formula I.    
     
     
         2 . A process of    claim 1    wherein the compounds of formula I and III are present in an enantiomeric excess of one enantiomer.  
     
     
         3 . A process of    claim 2    wherein the compounds of formula I and III are present in an enantiomeric excess of one enantiomer of at least 90% ee.  
     
     
         4 . A process of    claim 3    wherein the compounds of formula I and III are present in an enantiomeric excess of one of the enantiomers of at least 98% ee.  
     
     
         5 . A process of    claim 1   , wherein R 1  is aryl, heteroaryl, mono or di substituted aryl or mono or di substituted heteroaryl, wherein the substituents on the aryl or heteroaryl are independently selected from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, lower aralkyl, —NR 3   2 , wherein R 3  is a lower alkyl; R 4 —CONH, wherein R 4  is phenyl or a lower alkyl; and —OC(O)R6,wherein R 6  is hydrogen, alkyl or aralkyl  
     
     
         6 . A process of    claim 5   , wherein R 1  is phenyl, pyrimidyl, unsubstituted or substituted pyridyl, napthyl or 3,5-dichlorophenyl.  
     
     
         7 . A process of    claim 6   , wherein R 1  is 2-pyridyl, 3-pyridyl or 4-pyridyl.  
     
     
         8 . A process of    claim 7   , wherein R 1  is 3-pyridyl.  
     
     
         9 . A process of    claim 1   , wherein R 2  is a lower alkyl.  
     
     
         10 . A process of    claim 9   , wherein R 2  is methyl.  
     
     
         11 . A process of    claim 1   , wherein R 1  is 3-pyridyl and R 2  is methyl.  
     
     
         12 . A process of    claim 11    wherein the compounds of formula I and III are present in an enantiomeric excess of one enantiomer of at least 90% ee.  
     
     
         13 . A process of    claim 11   , wherein the inert solvent capable of azeotropic removal of water is xylene, heptane or toluene.  
     
     
         14 . A process of    claim 13   , further comprising reacting the compound of formula II with the compound of formula III to form the compound of formula IV in the presence of at least two equivalents of a carboxylic acid.  
     
     
         15 . A process of    claim 14   , wherein the carboxylic acid is acetic acid.  
     
     
         16 . A process of    claim 15   , further comprising washing the compound of formula IV with an aqueous base to remove excess acid.  
     
     
         17 . A process of    claim 15   , wherein the palladium catalyst is present in an amount of at least 10 weight percent of 20 percent palladium hydroxide on carbon.  
     
     
         18 . A process of    claim 1   , further comprising separating and isolating the compound of formula V into a desired diastereomer.  
     
     
         19 . A process of    claim 15   , further comprising separating and isolating the compound of formula V into a desired diastereomer.  
     
     
         20 . A process of    claim 15   , further comprising reacting the compound of formula V in formic acid, in the presence of a hydrosilane, to form the compound of formula I.  
     
     
         21 . A compound of formula IV  
                   wherein R 1  is aryl, heteroaryl, substituted aryl or substituted heteroaryl; R 2  is alkyl or aralkyl; R 5  is hydrogen or hydroxy; or a salt thereof.    
     
     
         22 . A compound of formula V  
                   wherein R 1  is aryl, heteroaryl, substituted aryl or substituted heteroaryl; R 2  is alkyl or aralkyl; R 5  is hydrogen or hydroxy; or a salt thereof.    
     
     
         23 . A process for preparing a compound of formula I  
                   wherein R 1  is aryl, heteroaryl, substituted aryl or substituted heteroaryl and R 2  is hydrogen, alkyl or aralkyl, or a salt thereof,    comprising reacting the compound of formula IV  
                 
   wherein R 1  is as described above, R 2′  is alkyl or aralkyl and R 5  is hydrogen or alkoxy, with hydrogen gas in the presence of a palladium catalyst to form the compound of formula V  
                 
   and reacting the compound of formula V to form the compound of formula I.