Process for Manufacture of N-acylbiphenyl alanine

Abstract

A novel process, novel process steps and novel intermediates useful in the synthesis of pharmaceutically active compounds, in particular neutral endopeptidase (NEP) inhibitors.

1 . A process for preparing a compound of formula (1-a), or salt thereof, 
       
         
           
           
               
               
           
         
         preferably wherein the compound of formula (1-a) is of the formula (1), 
       
       
         
           
           
               
               
           
         
         wherein R1 is C 1-7 alkyl, preferably methyl, or C 6-10 aryl, preferably phenyl, 
         comprising 
         reacting 
       
       
         
           
           
               
               
           
         
         or salt thereof, 
         with 
         a compound of formula (A), or salt thereof, 
       
       
         
           
           
               
               
           
         
         wherein R1 is as defined for the compound of formula (1-a), 
         and 
         (R2CO) 2 O, wherein R2 is C 1-7 alkyl, preferably methyl or propyl, 
         under alkaline conditions, 
         to provide the compound of formula (1-a). 
       
     
     
         2 . The process according to  claim 1 , wherein the alkaline conditions comprise the use of a base selected from triethylamine, pyridine, N-methylpyrrole, N-methylmorpholine, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium acetate, potassium acetate, sodium propionate and potassium propionate. 
     
     
         3 . The process according to  claim 1  ems, wherein the reaction is carried out at a temperature of from of from 80 deg C. to reflux. 
     
     
         4 . A process for preparing a compound of formula (2-a), or salt thereof, 
       
         
           
           
               
               
           
         
         preferably wherein the compound of formula (2-a) is of the formula (2), 
       
       
         
           
           
               
               
           
         
         wherein R1 is C 1-7 alkyl, preferably methyl, or C 6-10 aryl, preferably phenyl, 
         comprising 
         reacting 
         a compound of formula (1-a), or salt thereof, 
       
       
         
           
           
               
               
           
         
         preferably wherein the compound of formula (1-a) is of the formula (1), 
       
       
         
           
           
               
               
           
         
         wherein R1 is as defined for a compound of formula (2-a), 
         with water 
         to provide the compound of formula (2-a). 
       
     
     
         5 . The process according to  claim 4 , wherein the reaction is carried out at a temperature of from of from room temperature to reflux. 
     
     
         6 . A process for preparing a compound of formula (3), or salt thereof, 
       
         
           
           
               
               
           
         
         preferably wherein the compound of formula (3) is of the formula (3-a), 
       
       
         
           
           
               
               
           
         
         wherein R1 is C 1-7 alkyl, preferably methyl, or C 6-10 aryl, preferably phenyl, comprising 
         treating a compound of formula (2-a), or salt thereof, 
       
       
         
           
           
               
               
           
         
         preferably wherein the compound of formula (2-a) is of the formula (2), 
       
       
         
           
           
               
               
           
         
         wherein R1 is C 1-7 alkyl, preferably methyl, or C 6-10 aryl, preferably phenyl, 
         under hydrogenation conditions 
         to provide the compound of formula (3). 
       
     
     
         7 . The process according to  claim 6 , wherein the hydrogenation conditions comprise the use of hydrogen and palladium, preferably, palladium on charcoal. 
     
     
         8 . A process for preparing a compound of formula (3), as defined in  claim 6 ,
 comprising the steps of   i) preparing the compound of formula (1-a), as defined in  claim 1 , according to the process defined in  claim 1 ;   ii) preparing the compound of formula (2-a), as defined in  claim 4 , according to the process defined in  claim 4 ; and   iii) obtaining the compound of formula (3), according to the process defined in  claim 6 .   
     
     
         9 . A process for preparing a compound of formula (3), as defined in  claim 6 ,
 comprising the steps of   ii) preparing the compound of formula (2-a), as defined in  claim 4 , according to the process defined in  claim 4 ; and   iii) obtaining the compound of formula (3), according to the process defined in  claim 6 .   
     
     
         10 . A compound of formula (1-a), or salt thereof, 
       
         
           
           
               
               
           
         
         preferably wherein the compound of formula (1-a) is of the formula (1), 
       
       
         
           
           
               
               
           
         
         wherein R1 is C 1-7 alkyl, preferably methyl, or C 6-10 aryl, preferably phenyl. 
       
     
     
         11 . A compound of formula (2-a), or salt thereof, 
       
         
           
           
               
               
           
         
         preferably wherein the compound of formula (2-a) is of the formula (2), 
       
       
         
           
           
               
               
           
         
         wherein R1 is C 1-7 alkyl, preferably methyl, or C 6-10 aryl, preferably phenyl. 
       
     
     
         12 . A compound of formula (3), or salt thereof, 
       
         
           
           
               
               
           
         
         preferably wherein the compound of formula (3) is of the formula (3-a), 
       
       
         
           
           
               
               
           
         
         wherein R1 is C 1-7 alkyl, preferably methyl, or C 6-10 aryl, preferably phenyl.