Process and intermediates for the preparation of NEP inhibitors

Abstract

The present invention relates to a new chemical synthesis, intermediates and catalysts useful for the preparation of the neprilysin (NEP) inhibitor sacubitril. It further relates to new intermediate compounds and their use for said new chemical synthesis route.

The invention claimed is: 
     
       1. A compound of formula (1), or a salt thereof, 
       
         
           
           
               
               
           
         
         wherein R1 is hydrogen or C 1 -C 6 -alkyl. 
       
     
     
       2. The compound of the formula (1) according to  claim 1  represented by formula (1-a), 
       
         
           
           
               
               
           
         
         wherein R1 is hydrogen or C 1 -C 6 -alkyl. 
       
     
     
       3. A compound of formula (2), 
       
         
           
           
               
               
           
         
       
     
     
       4. The compound of formula (2) according to  claim 3  represented by formula (2-a), 
       
         
           
           
               
               
           
         
       
     
     
       5. A compound of formula (7), 
       
         
           
           
               
               
           
         
       
     
     
       6. A process for the manufacture of a compound of formula (1), 
       
         
           
           
               
               
           
         
         wherein R1 is hydrogen, or a salt thereof, comprising, oxidizing a compound of formula (2), 
       
       
         
           
           
               
               
           
         
       
       in the presence of an oxidant. 
     
     
       7. The process according to  claim 6 , further comprising the step of simultaneously or separately esterifying the obtained compound of formula (1), or a salt thereof, wherein R1 is hydrogen, with a C 1 -C 6 -aliphatic alcohol, to yield a compound of formula (1) wherein R1 is C 1 -C 6 -alkyl. 
     
     
       8. A process for the manufacture of a compound of Formula (2), 
       
         
           
           
               
               
           
         
       
       comprising, reacting a compound of formula (3), 
       
         
           
           
               
               
           
         
         with methacrolein, or a reactive derivative thereof, in the presence of an organocatalyst suitable for a Michael reaction, wherein the organocatalyst is selected from the group consisting of those represented by the following formulae: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       9. A process for the manufacture of a compound of formula (2), 
       
         
           
           
               
               
           
         
       
       comprising, reacting of a compound of formula (7), 
       
         
           
           
               
               
           
         
       
       with propionaldehyde, or a reactive derivative thereof, in the presence of an organocatalyst suitable for a Michael reaction, wherein the organocatalyst is selected from the group consisting of those represented by the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       10. The process according to  claim 8 , wherein the organocatalyst is selected from the group consisting of those represented by the following formulae: 
       
         
           
           
               
               
           
         
       
     
     
       11. A process for the manufacture of a compound of formula (7), 
       
         
           
           
               
               
           
         
       
       comprising, reacting a compound of formula (3), 
       
         
           
           
               
               
           
         
       
       with formaldehyde, or a reactive derivative thereof. 
     
     
       12. The process according to  claim 8 , further comprising a process for the manufacture of the compound of formula (3), 
       
         
           
           
               
               
           
         
       
       the process comprising, hydrogenating a compound of formula (4), 
       
         
           
           
               
               
           
         
       
       in the presence of an alkali metal borohydride capable of selectively reducing the double bond. 
     
     
       13. The process according to  claim 12 , further comprising a process for the manufacture of the compound of formula (4), 
       
         
           
           
               
               
           
         
       
       the process comprising, reacting a compound of formula (5), 
       
         
           
           
               
               
           
         
       
       with a dehydrating agent. 
     
     
       14. The process according to  claim 13 , further comprising a process for the manufacture of the compound of formula (5) or a mixture of the compound of formula (5) and the compound of formula (4), the process comprising reacting an aldehyde compound of formula (6), 
       
         
           
           
               
               
           
         
         or a reactive derivative thereof, with nitromethane. 
       
     
     
       15. A process for the manufacture of a compound of formula (8), 
       
         
           
           
               
               
           
         
         wherein R′ and R″ are independently of each other hydrogen or a nitrogen protecting group, and R1 is hydrogen or C 1 -C 6 -alkyl, comprising hydrogenating a compound of formula (1), or a salt thereof, 
       
       
         
           
           
               
               
           
         
         wherein R1 is hydrogen or C 1 -C 6 -alkyl, in the presence of Raney Nickel and optionally including or followed by the introduction of a nitrogen protecting group; and 
         wherein the obtained compound of formula (8) is optionally further reacted with succinic acid, or a derivative thereof to form a compound of formula (10), 
       
       
         
           
           
               
               
           
         
         wherein R1 is hydrogen or C 1 -C 6 -alkyl, thereof. 
       
     
     
       16. The process according to  claim 9 , wherein the organocatalyst is selected from the group consisting of those represented by the following formulae: