Process for the manufacture of hmg-coa reductase inhibitors

Abstract

The invention relates to a process for the manufacture of a compound of formula or a salt, especially a pharmaceutically acceptable salt with a base, thereof or a lactone thereof wherein the element represents —CH 2 —CH 2 — or —CH═CH— and R represents a cyclic residue.

1 . A process for the manufacture of an enantiomerically pure form or a racemic form of a compound of formula 
       
         
           
           
               
               
           
         
       
       or a salt, especially a pharmaceutically acceptable salt with a base, thereof or a lactone thereof wherein the element   represents —CH 2 —CH 2 — or —CH═CH— and R represents a cyclic residue; comprising
 (a) reacting compounds (III a) or (III b) 
 
       
         
           
           
               
               
           
         
       
       wherein X 4  and X 5 , independently of one another, represents C 1 -C 7 -alkyl or phenyl-C 1 -C 7 -alkyl;
 X 6 , X 7  and X 8 , independently of one another, represent phenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of C 1 -C 7 alkyl, hydroxy, C 1 -C 7 alkoxy, C 2 -C 8 alkanoyl-oxy, halogen, nitro, cyano, and CF 3 ; and Hal −  represents a halide anion; 
 
       with a metallated alkane to form the corresponding ylide and then reacting the resulting ylide intermediate with a compound of formula 
       
         
           
           
               
               
           
         
       
       wherein
 X represents etherified hydroxy, esterified hydroxy, or unsubstituted or mono- or di-substituted amino; 
 X 1  is protected hydroxy; 
 X 2  represents C 1 -C 7 alkyl; and 
 X 3  represents hydrogen or one or more substituents, e.g. selected from the group consisting of C 1 -C 7 alkyl, hydroxy, C 1 -C 7 alkoxy, C 2 -C 8 alkanoyl-oxy, halogen, nitro, cyano, and CF 3 ; 
 (b) optionally, if desired, converting a resulting compound of formula (III d) 
 
       
         
           
           
               
               
           
         
       
       wherein X 1 , X 2  and X 3  have the meanings as defined above and Y represents a group of formula (X 4 O)(X 5 O)P(═O)— or (X 6 )(X 7 )(X 8 )P +  Hal −  and X 4 , X 5 , X 6 , X 7 , X 8  and Hal −  have the meanings as defined above; 
       into a compound of formula (III e) 
       
         
           
           
               
               
           
         
       
       wherein X 2 , X 3  and Y, have the meaning as defined above and wherein Y 1  represents hydroxy or protected hydroxy and Y 2  is hydrogen and Y 3  is hydroxy or protected hydroxy, and Y 1  and Y 3  forming a syn-diol configuration; or wherein 
       Y 1  and Y 3  together represent —O-Alk-O— and Alk being C 1 -C 7 alkylidene; and Y 2  is hydrogen, and Y 1  and Y 3  forming a syn-diol configuration;
 (c) reacting a compound of formula (III e) 
 
       wherein X 2 , X 3  and Y, have the meaning as defined above and wherein 
       Y 1  represents hydroxy or protected hydroxy and Y 2  is hydrogen and Y 3  is hydroxy or protected hydroxy, and Y 1  and Y 3  forming a syn-diol configuration; or wherein 
       Y 1  and Y 3  together represent —O-Alk-O— and Alk being C 1 -C 7 alkylidene; and Y 2  is hydrogen, and Y 1  and Y 3  forming a syn-diol configuration; or wherein 
       Y 1  and Y 2  together represent the oxo group and Y 3  represents protected hydroxyl (corresponding to compounds of formula (II d); 
       with an aldehyde of formula (III f) R—CH(═O) resulting in a compound of formula (III g) 
       
         
           
           
               
               
           
         
       
       wherein R, X 2 , X 3 , Y 1 , Y 2  and Y 3  and the element   have the meanings as defined above; 
       if desired, reducing corresponding compounds of formula (III g), wherein the element   is —CH═CH— to result in a compound wherein said element is —CH 2 —CH2—; and
 (d) if a compound of formula (III g) is obtained, wherein one of Y 1  and Y 3  is protected hydroxy and the other is hydroxy or both of Y 1  and Y 3  is protected hydroxy and, in each case Y 2  is hydrogen; and Y 1  and Y 3  are forming the syn configuration; or 
 Y 1  and Y 3  together represent —O-Alk-O— and Alk being C 1 -C 7 alkylidene and Y 1  and Y 3  are forming the syn configuration; and Y 2  is hydrogen; or 
 
       by removing the hydroxy protection group(s) to a compound of formula 
       
         
           
           
               
               
           
         
       
       if desired, reducing corresponding compounds of formula (III h), wherein the element   is —CH═CH— to result in a compound wherein said element is —CH 2 —CH 2 —;
 (e) if a compound of formula (III g) is obtained, wherein Y 1  and Y 2  together form the oxo group ═O; and Y 3  is protected hydroxy (X 1 ); converting said compound of formula (III g), to a compound of formula (III i) 
 
       
         
           
           
               
               
           
         
       
       by removing the hydroxy protection group; 
       wherein R, X 2 , X 3  and the element   have the meanings as defined above; and subsequent reduction of said compound of formula (III i) to a compound of formula (III h);
 (f) hydrolyzing a compound of formula (III h) to a compound of formula (I) or a salt thereof and 
 (g) isolating a resulting compound of formula (I) or a salt thereof; 
 
       and, if desired, converting a resulting free acid of formula (I) into a salt thereof or into a lactone of formula (I a) or (I b), respectively, or converting a resulting lactone of a formula (I a) or (I b) into an acid of formula (I) or a salt thereof. 
     
     
         2 . A process according to  claim 1  for the manufacture of a compound of formula (I) or a salt thereof, wherein the element   represents —CH═CH— and R represents the cyclic residue of formula 
       
         
           
           
               
               
           
         
       
     
     
         3 . A process according to  claim 1 , wherein a compound selected from the group consisting of a compound of formulae (IIIc), (IIId), (IIIe), (IIIg), (IIIh), and (IIIi) is used, wherein, in each case, X 2  is methyl and X 3  is hydrogen. 
     
     
         4 . A process according to  claim 1 , wherein a compound of formula (IIIc) is used, wherein X is N—C 1 -C 7 alkyl-N—C 1 -C 7 alkoxy-amino. 
     
     
         5 . A process according to  claim 1 , wherein a compound selected from the group consisting of a compound of formulae (IIIc) and (IIId) is used, wherein X 1  is tert-butyl-dimethyl-silyloxy, and from the group consisting of a compound of formulae (IIIe), (IIIg) and (IIIh), is used, wherein Y 3  is tert-butyl-dimethyl-silyloxy.