Convergent synthesis of renin inhibitors and intermediates useful therein

Abstract

Described is a method for the preparation of renin inhibitors such as aliskiren, and intermediates useful therein. The method introduces a nitrogen-containing intermediate such as a lactone of formula (8). with R 4 being a branched C 3-6 alkyl. In the preparation of the lactone, or related intermediates, a desired stereochemical configuration can be controlled by starting from a chiral aldehyde satisfying formula (10).

1 . A compound selected from the group consisting of the compounds satisfying the following formulae (7a) through (7h): 
       
         
           
           
               
               
           
         
         wherein 
         R 4  is a branched C 3-6  alkyl; 
         R 6  represents H, or optionally substituted C 1-12 alkyl, optionally substituted C 1-12  alkylaryl, or optionally substituted C 1-12 aryl; 
         R 7  represents H, or is an O-protecting group; or R 6  forms with R 7  an optionally substituted C 1-12 (hetero)cyclic compound, as such protecting both the acid and alcohol group; 
         Z is a N-protecting group; 
         R 11  is a O-protecting group; 
         R 12  and R 13  are either the same or different fragments, chosen from the group of H, optionally substituted C 1-12 alkyl, optionally substituted C 1-12 alkylaryl and optionally substituted C 1-12 aryl, or R 12  and R 13  are joined together in a C 1-20 (hetero)cyclic structure; 
         Ra +  is a counter-cation; and 
         St is a group capable of stabilising the imine. 
       
     
     
         2 . A compound according to formula (8), selected from the group consisting of the compounds satisfying the following formulae: 
       
         
           
           
               
               
           
         
         wherein 
         R 4  is a branched C 3-6  alkyl; 
         Z is a N-protecting group; 
         R 11  is a O-protecting group; 
         R 12  and R 13  are either the same or different fragments, chosen from the group of H, optionally substituted C 1-12  alkyl, optionally substituted C 1-12 alkylaryl and optionally substituted C 1-12  aryl, or R 12  and R 13  are joined together in a C 1-20 (hetero)cyclic structure; 
         Ra +  is a counter-cation; and 
         St is a group capable of stabilising the imine. 
       
     
     
         3 . A compound according to  claim 1  or  2 , wherein R 4  is 2-propyl. 
     
     
         4 . A method for the preparation of a compound according to  claim 1  or  2  comprising at least the following step:
 reacting an aldehyde satisfying formula (10) 
 
       
         
           
           
               
               
           
         
         with R 4  and R 6  having the meaning as indicated above, with a cyanide, under appropriate conditions. 
       
     
     
         5 . A method according to  claim 4 , wherein the reaction is conducted in the presence of a chiral catalyst. 
     
     
         6 . A method according to  claim 5 , wherein the chiral catalyst is an enzyme. 
     
     
         7 . A method according to  claim 6 , wherein the enzyme hydroxynitrile lyase. 
     
     
         8 . A method for the preparation of a compound satisfying formula (9a) or (11a) or a mixture thereof, 
       
         
           
           
               
               
           
         
         comprising at least the following steps: 
         a) reacting a compound according to formula (2a) 
       
       
         
           
           
               
               
           
         
         
           wherein R 1  is selected from the group consisting of F, Cl, Br, I, C 1-6 halogenalkyl, C 1-6 alkoxy-C 1-6 alkyloxy, and C 1-6 alkoxy-C 1-6 alkyl; R 2  is selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl or C 1-4 alkoxy; 
           R 3  is a branched C 3-6  alkyl; and Re denotes a reactive moiety selected from F; Cl; Br; I; M(X) n , wherein X is F, Cl, Br, I, CN, C 1-12 alkyl, or C 1-6 alkoxy and M is a metal, preferably M is Mg, Ce, Li, Ba, Al, B, Cu, Zn, Mn, Ti, Zr, In and n is 0, 1, 2, 3, or 4; MM′(X) n (Y) n′ , wherein M and M′ are a metal, preferably M and M′ are each independently Mg, Ce, Li, Ba, Al, B, Cu, Zn, Mn, Ti, Zr, In, where X and Y are each independently chosen from F, Cl, Br, I, or CN, C 1-12 alkyl, C 1-6 alkoxy and n, n′ are each independently chosen from the values as described above for n; 
         
         with a second compound selected from the group consisting of the compounds satisfying the following formulae (7a) through (7h): 
       
       
         
           
           
               
               
           
         
         wherein R 4  is a branched C 3-6  alkyl; Z is a N-protecting group; R 11  is a O-protecting group; R 12  and R 13  are either the same or different fragments, chosen from the group of H, optionally substituted C 1-12 alkyl, optionally substituted C 1-12 alkylaryl and optionally substituted C 1-12 aryl, or R 12  and R 13  are joined together in a C 1-20 (hetero)cyclic structure; Ra +  is a counter-cation; and St is a group capable of stabilising the imine, 
         b) followed by stereoselective hydrogenation of the C═C double bond, originating from compound according to formula (2a). 
       
     
     
         9 . A compound according to formula (6a) and (6b), 
       
         
           
           
               
               
           
         
         wherein R 4  is a branched C 3-6  alkyl; R 6  represents H, or optionally substituted C 1-12 alkyl, optionally substituted C 1-12  alkylaryl, or optionally substituted C 1-12 aryl; and R 7  represents H, or is an O-protecting group; or R 6  forms with R 7  an optionally substituted C 1-12 (hetero)cyclic compound, as such protecting both the acid and alcohol group. 
       
     
     
         10 . A compound selected from the group consisting of the compounds satisfying the following formulae (8a) through (8h): 
       
         
           
           
               
               
           
         
         wherein R 4  is 2-propyl, Z is a N-protecting group; R 11  is a O-protecting group; R 12  and R 13  are either the same or different fragments, chosen from the group of H, optionally substituted C 1-12 alkyl, optionally substituted C 1-12 alkylaryl and optionally substituted C 1-12 aryl, or R 12  and R 13  are joined together in a C 1-20 (hetero)cyclic structure; and Ra +  is a counter-cation.