Process for the manufacture of hmg-coa reductase inhibitory mevalonic acid derivatives

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 radical.

1 . A process for the manufacture of a compound of formula  
     
       
         
         
             
             
         
       
     
     or a salt thereof or a lactone thereof, wherein the element   represents —CH 2 —CH 2 — or —CH═CH— and R represents a cyclic residue, according to the present inventions is characterized by 
 (a) reacting a compound of formula (IIa)  
                     
 wherein R 1 , R 2  and R 3 , independently of one another, represents phenyl that is un-substituted 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 R 4  is an aliphatic, cycloaliphatic, araliphatic or aromatic residue;  
 with a compound of formula R—CH(═O) (IIb) wherein R represents a cyclic residue; and  
 (b) reducing a resulting compound of formula (IIc)  
                     
 wherein R and R 4  have the meanings as defined above; in the presence of a reducing agent selected from the group consisting of a compound of formulae (IId), (IId′), (IId″), (IId′″), (IId″″), (IId′″″), (IId″″″), and (IId′″″″)  
                                                         
 wherein  
 M is Ru, Rh, Ir, Fe, Co or Ni;  
 L 1  is hydrogen;  
 L 2  represents an aryl or aryl-aliphatic residue;  
 Hal is halogen;  
 R 5  is an aliphatic, cydoaliphatic, cycloaliphatic-aliphatic, aryl or ary-aliphatic residue, which, in each case, may be linked to a polymer;  
 each of R 6  and R 7 , independently, is an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl or aryl-aliphatic residue;  
 each of R 8  and R 9  is phenyl or R 8  and R 9  form together with the carbon atom to which they are attached a cyclohexane or cyclopentane ring; and  
 R 15  is H, halogen, amino, nitro or C 1 -C 7 alkoxy;  
 wherein any aromatic residue of a compound of formula (IId), (IId′), (IId″), (IId′″), (IId″″), (IId′″″), (IId″″″) or (IID′″″″) is unsubstituted or substituted;  
 wherein for compounds of formula (IId″), (IId′″), (IId″″), (IId′″″), (IId″″″) or (IID′″″″) also combinations with (R)— or (S)—BINAP are possible; and  
 (c) condensing a resulting compound of formula (IIe)  
                     
 wherein R and R 4  have the meanings as defined above,  
 with a compound of formula (IIf)  
                     
 wherein R 16  represents an aliphatic residue, and  
 (d) reducing a resulting compound of formula (IIg)  
                     
 wherein R and R 16  have the meanings as defined above, and  
 (e) hydrolysing a resulting compound of formula (IIh)  
                     
 wherein R and R 16  have the meanings as defined above, and  
 (f) 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 (Ia) or (Ib), respectively, or converting a resulting lactone of a formula (Ia) or (Ib) into an acid of formula (I) or a salt thereof, or converting a resulting compound of formula (I) wherein the element   represents —CH═CH— into a compound of formula (I) wherein the element   represents —CH 2 —CH 2 —.  
 
   
   
       2 . A process according to  claim 1 , wherein a compound of formulae (IIa), (IIc), (IIe), (IIg) and (IIh) is used, wherein R 4  or R 16 , respectively, represent C 1 -C 4 alkyl, especially methyl or ethyl or most preferably tert-butyl.  
   
   
       3 . A process for the manufacture of a compound of formula (IIe)  
     
       
         
         
             
             
         
       
     
     wherein R and R 4  have the meanings as defined above, characterized by reducing a resulting compound of formula (IIc)  
     
       
         
         
             
             
         
       
     
     wherein R and R 4  have the meanings as defined above; in the presence of a reducing agent of formula  
     
       
         
         
             
             
         
       
     
     wherein M, L 1 , L 2 , R 8  and R 9  are as defined above and R 5  is a group of formula  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein 
 n is 0 , 2, 3, 4, 5, 6 or 7;  
 X is O or S;  
 R 10  is polystyrol;  
 R 11  is silica gel;  
 R 12  is cross-linked polystyrol;  
 R 13  is polyethylene-glycol;  
 R 14  is C 1 -C 6 alkyl; and  
 m is 1, 2 or 3.  
 
   
   
       4 . A compound of formula (IId), wherein L 1  is hydrogen and L 2  represents phenyl or phenyl substituted by one, two, three, four or five alkyl residues, especially by once by isopropyl such as 4-isopropyl-phenyl, and R 5  represents a residue selected from the group consisting of 2- or 3- or 4-pyridyl, 4-chloro-4-phenoxy-phenyl, 4-phenoxy-phenyl, 5-di(m)ethylamino-1-naphthyl, 5-nitro-1-naphthyl, 2-, 3-, 4-nitrophenyl, 4-vinylphenyl, 4-biphenylyl, 9-anthracenyl, 2,3-, 4-hydroxyphenyl, tolyl, phenanthryl, benzo[1,3]-dioxole, dimethyl(naphthalene-1-yl)-amine, mono to tristrifluoromethylphenyl, chrysenyl, perylenyl and pyrenyl or 2-phenylethene.  
   
   
       5 . A compound of formula (IId″) and (IId′″), wherein Hal is each case is chloro; R 6  and R 7 , in each case, represents phenyl or phenyl substituted by one or more C 1 -C 7 alkyl, especially 3,5-dimethylphenyl.  
   
   
       6 . A compound of formula (IId″″) and (IId′″″), wherein Hal is each case is chloro; R 6  and R 7 , in each case, represents phenyl or phenyl substituted by one or more C 1 -C 7 alkyl, especially represents 3,5-dimethylphenyl.  
   
   
       7 . A compound of formula (IId′″″) and (IId″″″), wherein Hal is each case is chloro; R 6  and R 7 , in each case, represents phenyl or phenyl substituted by one or more C 1 -C 7 alkyl, especially represents 3,5-dimethylphenyl.