Process for producing simvastatin and/or its derivatives

Abstract

A process for the production of simvastatin and its analogues that is efficient, economical and convenient involves the use of hydroxyl protected intermediates of formula (III) or (VII). These intermediates allow for direct alkylation of the butyrate side chain followed by deprotection and reformation of the lactone ring. R 1 is hydrogen or methyl; R 2 represents a straight or branched chain alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an aralkyl group having I to 6 carbon atoms in the alkyl chain; R 3 and R 4 each independently represent an alkyl group, an ether group, a thioether group, an aryl group, an aralkyl group, an alkenyl group, a cyclic ether group, or a cyclic thioether group; and R 5 and R 6 each independently represent hydrogen, an alkyl group, an aryl group, an aralkyl group, an alkoxy group, or an ether group.

We claim:  
     
         1 . A process, which comprises reacting a compound of formula (II):  
       
         
           
           
               
               
           
         
       
       wherein R 1  represents hydrogen or methyl and R 2  represents a straight or branched chain alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an aralkyl group having 1 to 6 carbon atoms in the alkyl chain; with a protecting agent to form a compound of formula (III) or (VII):  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are as defined above in formula (II), R 3  and R 4  each independently represent an alkyl group, an ether group, a thioether group, an aryl group, an aralkyl group, an alkenyl group, a cyclic ether group, or a cyclic thioether group, and R 5  and R 6  each independently represent hydrogen, an alkyl group, an aryl group, an aralkyl group, an alkoxy group, or an ether group.  
       
     
     
         2 . The process according to  claim 1 , wherein a compound of formula (III) is formed.  
     
     
         3 . The process according to  claim 2 , wherein R 3  and R 4  represent a cyclic ether group or a cyclic thioether group.  
     
     
         4 . The process according to  claim 3 , wherein R 3  and R 4  are selected from the group consisting of a tetrahydropyranyl, an alkoxytetrahydropyranyl, a tetrahydrothiopyranyl, a dioxanyl, and tetrahydrofuranyl.  
     
     
         5 . The process according to  claim 2 , wherein R 3  and R 4  represent an alkyl group, an ether group, a thioether group, an aryl group or an aralkyl group.  
     
     
         6 . The process according to  claim 5 , wherein R 3  and R 4  represent an alkyl group.  
     
     
         7 . The process according to  claim 2 , wherein R 3  and R 4  are selected from the group consisting of methyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl, 1-ethoxyethyl, t-butyl, allyl, benzyl, tetrahydropyran-2-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydropyran-2-yl, 1,4-dioxan-2-yl and tetrahydrofuran-2-yl  
     
     
         8 . The process according to  claim 1 , wherein a compound of formula (VII) is formed.  
     
     
         9 . The process according to  claim 7 , wherein R 5  and R 6  represent hydrogen or a lower alkyl group.  
     
     
         10 . The process according to  claim 1 , wherein R 5  and R 6  are selected from the group consisting of hydrogen, methyl, phenyl, benzyl, methoxy, ethoxy, and methoxymethyl.  
     
     
         11 . The process according to  claim 1 , wherein R 2  is methyl or ethyl.  
     
     
         12 . The process according to  claim 1 , wherein said protecting agent is a dihyhropyran compound and R 3  and R 4  both represent the same tetrahydropyranyl group.  
     
     
         13 . The process according to  claim 1 , which further comprises alkylating said formed compound of formula (III) or (VII) to form a compound of formula (IV) or (VIII), respectively:  
       
         
           
           
               
               
           
         
       
       wherein R 7  represents methyl or ethyl.  
     
     
         14 . The process according to  claim 13 , wherein said alkylating is carried out by subjecting said compound of formula (III) or (VII) to a compound of the formula R 7 -X, wherein X is chlorine, bromine or iodine, in the presence of a base.  
     
     
         15 . The process according to  claim 13 , which further comprises deprotecting said alkylated compound of formula (IV) or (VIII) to form a compound of formula (V):  
       
         
           
           
               
               
           
         
       
     
     
         16 . The process according to  claim 15 , wherein said deprotection is carried out by hydrolyzing the protecting groups in an acidic medium.  
     
     
         17 . The process according to  claim 15 , which further comprises hydrolysis of the amide moiety of the compound of formula (V) and relactonization to produce a compound of formula (VI):  
       
         
           
           
               
               
           
         
       
     
     
         18 . The process according to  claim 17 , wherein R 7  is methyl and R 1  is methyl.  
     
     
         19 . The process according to  claim 1 , which further comprises reacting a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       with an amine of the general formula R 2 NH 2  to produce said compound of formula (II).  
     
     
         20 . A process which comprises: 
 (a) reacting a compound of formula (I) with an amine compound of the formula R 2 NH 2  to form a compound of formula (II):                          wherein R 1  represents hydrogen or methyl and R 2  represents methyl, ethyl, propyl, or butyl;    (b) reacting said compound of formula (II) with a protecting agent to form a compound of formula (III) or (VII):                          wherein R 3  and R 4  are the same and each represents a tetrahydropyranyl group, a tetrahydrofuranyl group or a dioxanyl group, and R 5  and R 6  are both the same and each represents hydrogen, methyl, ethyl, propyl, butyl, phenyl or benzyl;    (c) alkylating said compound of formula (III) or (VII) formed in said step (b) by treating with an alkali metal amide and methyliodide to form a compound of formula (IV) or (VIII), respectively:                          wherein R 7  is methyl;    (d) deprotecting said compound produced in step (c) by acidic hydrolysis to form a compound of formula (V):    and (e) hydrolyzing the amidic moiety of said compound of formula (V)                          and relactonizing to obtain a compound of formula (VI):                          
     
     
         21 . A compound of formula (III) (IV), (VII), or (VIII):  
       
         
           
           
               
               
           
         
       
       wherein R 1  is hydrogen or methyl; R 2  represents a straight or branched chain alkyl  
       
         
           
           
               
               
           
         
       
       group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an aralkyl group having 1 to 6 carbon atoms in the alkyl chain; R 3  and R 4  each independently represent an alkyl group, an ether group, a thioether group, an aryl group, an aralkyl group, an alkenyl group, a cyclic ether group, or a cyclic thioether group; R 5  and R 6  each independently represent hydrogen, an alkyl group, an aryl group, an aralkyl group, an alkoxy group, or an ether group; and R 7  represents methyl or ethyl.  
     
     
         22 . The compound according to  claim 21 , wherein said compound is selected from the group consisting of: 
 lovastatin ethylamide bis-tetrahydropyran-2-ylether;    lovastatin n-butylamide bis-tetrahydropyran-2-ylether;    lovastatin ethylamide acetonide;    lovastatin butylamide acetonide;    Simvastatin ethylamide bis-tetrahydropyran-2-ylether;    Simvastatin n-butylamide bis-tetrahydropyran-2-ylether;    Simvastatin ethylamide acetonide; and    Simvastatin butylamide acetonide.    
     
     
         23 . A compound of the formula (V):  
       
         
           
           
               
               
           
         
       
       wherein R 1  represents hydrogen or methyl, R 2  represents methyl or ethyl, and R 7  represents methyl or ethyl.