Organic compounds

Abstract

The invention provides a novel process, novel process steps and novel intermediates useful in the synthesis of pharmaceutically active compounds, especially renin inhibitors, such as Allskiren. Inter alia, the invention provides a process for the manufacture of a compound of the formula III, wherein R, R 1 , R 2 , R 3 and PG are as defined in the specification, or a salt thereof. The manufacture comprises (preferably consists of) reacting a compound of the formula I, with a reagent able to transform hydroxy into X where X is for example a leaving group.

1 - 2 . (canceled) 
     
     
         3 . A compound of the formula III 
       
         
           
           
               
               
           
         
       
       wherein
 R is hydrogen, alkyl or alkoxyalkyl, preferably C 1 -C 7 -alkoxy, especially methoxy; 
 R 1  is hydrogen, alkyl or alkoxyalkyl, C 1 -C 7 -alkoxy-C 1 -C c -alkyl, especially 3-methoxypropyl; 
 R 2  is hydrogen or preferably a hydroxyl protecting group; 
 R 3  is hydrogen or unsubstituted or substituted alkyl; and 
 PG is an amino protecting group, especially one removable by hydrolysis, e.g. lower alkoxycarbonyl, such as tert-butoxycarbonyl; 
 or a salt thereof. 
 
     
     
         4 . A compound of the formula I 
       
         
           
           
               
               
           
         
       
       wherein R, R 1 ,R 2 ,R 3  and PG are as defined in  claim 3  preferably wherein the compound of formula I is (1S, 3S, 5S)-5-tert-butoxycarbonyloxymethyl-3-isopropyl-2-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]pyrrolidine-1-carboxylic acid tert-butyl ester, or a salt thereof. 
     
     
         5 . A process for the manufacture of a compound of the formula IV, 
       
         
           
           
               
               
           
         
       
       wherein R, R 1 , R 3  and PG are as defined under formula III in  claim 3  or a salt thereof, comprising removing a hydroxy protecting group R 2  in a compound of the formula III, or a salt thereof. 
     
     
         6 . A compound of the formula IV, 
       
         
           
           
               
               
           
         
       
       wherein
 R, R 1 , R 2 , R 3 , and PG are as defined in  claim 3 ; 
 or a salt thereof. 
 
     
     
         7 . A compound of the formula IV according to  claim 5  with the name (2R, 3S, 5S)-5-hydroxymethyl-3-isopropyl-2-[4-methoxy-3-(3 methoxy-propoxy)-phenyl]pyrrolidine-1-carboxylic acid tert-butyl ester, or a salt thereof. 
     
     
         8 . A process for the manufacture of a compound of the formula IVa, 
       
         
           
           
               
               
           
         
       
       wherein
 R, R 1 , R 2 , R 3  and PG are as defined in  claim 3 ; 
 or a salt thereof; 
 said process comprising removing a protecting groups R 2  and PG in a compound of the formula I, or a salt thereof and to form the pyrrolidine ring, 
 
       
         
           
           
               
               
           
         
       
       wherein R, R 1 , R 2  and R 3  are as defined for a compound of the formula III and PG is an amino protecting group, especially one removable by hydrolysis, e.g. lower alkoxycarbonyl, such as tert-butoxycarbonyl or benzyloxycarbonyl. 
     
     
         9 . A process for the manufacture of a compound of the formula IV, 
       
         
           
           
               
               
           
         
       
       wherein
 R, R 1 , R 2 , R 3  and PG are as defined in  claim 3 ; 
 or a salt thereof; 
 said process comprising protecting the a pyrrolidine nitrogen with a protecting weeps group PG in a compound of the formula (IVa), or a salt thereof 
 
       
         
           
           
               
               
           
         
       
       wherein R, R 1 , R 2  and R 3  are as defined for a compound of the formula III. 
     
     
         10 . A process for the manufacture of an oxo compound of the formula V. 
       
         
           
           
               
               
           
         
       
       wherein R, R 1 , R 3  and PG are as defined under formula III in  claim 3 , or a salt thereof, comprising oxidizing a compound of the formula IV, or a salt thereof, where in the case that R 3  in a compound of the formula IV is hydrogen the oxidation can take place directly to the oxo compound of the formula V or by oxidizing first to an acid of the formula XVI 
       
         
           
           
               
               
           
         
       
       wherein R, R 1  and PG are as defined above for a compound of the formula V, or a salt thereof, which is then reduced with a reducing agent to the corresponding aldehyde of the formula V wherein R 3  is hydrogen and the other moieties are as mentioned above. 
     
     
         11 . A compound of the formula XVI according to  claim 10 , wherein
 R is hydrogen, alkyl or alkoxyalkyl, preferably C 1 -C 1 -alkoxy, especially methoxy;   R 1  is hydrogen, alkyl or alkoxyalkyl, C 1 -C 7 -alkoxy-C 1 -C 7 alkyl, especially 3-methoxypropyl; and   PG is an amino protecting group,   or a salt thereof.   
     
     
         12 . A compound of the formula XVI according to  claim 11  with the name (2R, 3S, 5S)-4-isopropyl-5-[4-methoxy-3-(3 methoxy-propoxy)-phenyl]pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester, or a salt thereof. 
     
     
         13 . A compound of the formula V according to  claim 10 , wherein
 R is hydrogen, alkyl or alkoxyalkyl, preferably C 1 -C 7 -alkoxy, especially methoxy;   R 1  is hydrogen, alkyl or alkoxyalkyl, C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl, especially 3-methoxypropyl;   R 3  is hydrogen or unsubstituted or substituted alkyl; and   PG is an amino protecting group, especially one removable by hydrolysis, e.g. lower alkoxycarbonyl, such as tert-butoxycarbonyl;   or a salt thereof.   
     
     
         14 . A compound of the formula V according to  claim 13 , wherein the compound is (2R, 3S, 5S)-5-formyl-3-isopropyl-2-[4-methoxy-3-(3 methoxy-propoxy)-phenyl]pyrrolidine-1-carboxylic acid tert-butyl ester, or a salt thereof. 
     
     
         15 . A process for the manufacture of a compound of the formula VII, 
       
         
           
           
               
               
           
         
       
       wherein R, R 1  and PG are as defined under formula III in  claim 3  and PT is a hydroxyl protecting group, comprising reacting a compound of the formula V, wherein
 R is hydrogen, alkyl or alkoxyalkyl, preferably C 1 -C 7 -alkoxy, especially methoxy; 
 R 1  is hydrogen, alkyl or alkoxyalkyl, C 1 -C 7 -alkoxy-C 1 -C c -alkyl, especially 3-methoxypropyl; 
 R 3  is hydrogen; and 
 PG is an amino protecting group, especially one removable by hydrolysis, e.g. lower alkoxycarbonyl, such as tert-butoxycarbonyl; or a salt thereof under Grignard or Grignard-like conditions with a reagent prepared by reaction of a compound of the formula VI, 
 
       
         
           
           
               
               
           
         
       
       wherein Hal is halo and PT is a hydroxyl protecting group, with a metal. 
     
     
         16 . A compound of the formula VII according to  claim 15  wherein
 R is hydrogen, alkyl or alkoxyalkyl, preferably C 1 -C 7 -alkoxy, especially methoxy;   R 1  is hydrogen, alkyl or alkoxyalkyl, C 1 -C 7 -alkoxy-C 1 -C c -alkyl, especially 3-methoxypropyl;   R 3  is hydrogen; and   PG is an amino protecting group, especially one removable by hydrolysis, e.g. lower alkoxycarbonyl, such as tert-butoxycarbonyl; or a salt thereof.   
     
     
         17 . A compound of the formula VII according to  claim 16  wherein the compound is (2R, 3S, 5S)-5-((1S, 3S)-3-Benzoyloxymethyl-1-hydroxy-4-methyl-pentyl)-3-isopropyl-2-[4-methoxy-3-(3 methoxy-propoxy)-phenyl]pyrrolidine-1-carboxylic acid tert-butyl ester, or a salt thereof. 
     
     
         18 . A process for the manufacture of a compound of the formula VIII, 
       
         
           
           
               
               
           
         
       
       wherein R, R 1  and PG are as defined for a compound of the formula III in  claim 3 , or a salt thereof, comprising deprotecting a compound of the formula VII under removal of the hydroxy protecting group PT. 
     
     
         19 . A compound of the formula VIII according to  claim 18 , or a salt thereof, wherein
 R is hydrogen, alkyl or alkoxyalkyl, preferably C 1 -C 7 -alkoxy, especially methoxy;   R 1  is hydrogen, alkyl or alkoxyalkyl, C 1 -C 7 -alkoxy-C 1 -C c -alkyl, especially 3-methoxypropyl; and   PG is an amino protecting group, or a salt thereof.   
     
     
         20 . A compound of the formula VIII according to  claim 19 , wherein the compound is (2R, 3S, 5S)-5-((1S, 3S)-1-hydroxymethyl-3-hydroxymethyl-4-methyl pentyl)-3-isopropyl-2-[4-methoxy-3-(3 methoxy-propoxy)-phenyl]pyrrolidine-1-carboxylic acid tert-butyl ester, or a salt thereof. 
     
     
         21 . A process for the manufacture of a lactol of the formula X, 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R and PG are as defined for a compound of the formula III in  claim 3 , or a salt thereof, comprising
 oxidizing a compound of the formula VIII, or a salt thereof, at the primary hydroxy group to an aldehyde compound of the formula IX, 
 
       
         
           
           
               
               
           
         
       
       wherein R, R 1  and PG are as defined under formula X above, or a salt thereof, which then cyclizes spontaneously to produce a lactol of the formula X, or a salt thereof. 
     
     
         22 . A lactol of the formula X according to  claim 21 , or a pharmaceutically acceptable salt thereof, wherein
 R is hydrogen, alkyl or alkoxyalkyl, preferably C 1 -C 7 alkoxy, especially methoxy;   R 1  is hydrogen, alkyl or alkoxyalkyl, C 1 -C 7 -alkoxy-C 1 -C c -alkyl, especially 3-methoxypropyl; and   PG is an amino protecting group, or a salt thereof.   
     
     
         23 . A lactol of the formula X according to  claim 22 , wherein the compound is (2R, 3S, 5S)-6-((2S, 4S)-5-hydroxy-4-isopropyl-tetrahydra-furan-2-yl)-3-isopropyl-2-[4-methoxy-3-(3-methoxypropoxy)-phenyl[-pyrolidine-1-carboxylic acid tert-butyl ester, or a salt thereof. 
     
     
         24 . An aldehyde compound of the formula IX according to  claim 21 , or a pharmaceutically acceptable salt thereof, wherein
 R is hydrogen, alkyl or alkoxyalkyl, preferably C 1 -C 7 -alkoxy, especially methoxy;   R 1  is hydrogen, alkyl or alkoxyalkyl, C 1 -C 7 -alkoxy-C 1 -C c -alkyl, especially 3-methoxypropyl; and   PG is an amino protecting group, or a salt thereof.   
     
     
         25 . An aldehyde compound of the formula IX according to  claim 24 , wherein the compound is (2R,3S,5S)-5-((1S,3S)-3-Formyl-1-hydroxy-4-methyl-pentyl)-2-[4-hydroxy-3-(3-methoxy-propoxy)-phenyl]-3-isopropyl-pyrrolidine-1-carboxylic acid tert-butyl ester, or a salt thereof. 
     
     
         26 - 65 . (canceled)