Process for preparing simvastatin having controlled ranges of simvastatin dimer content

Abstract

The present invention relates to a process for preparing simvastatin, wherein the simvastatin dimer content is controlled. More particularly, the present invention relates to a process for preparing simvastatin having a simvastatin dimer content of about 0.2 to about 0.4 % wt. The present invention also relates to a process for preparing simvastatin having a simvastatin dimer content of less than about 0.2% wt. The present invention also discloses a commercial scale process of preparing simvastatin having a specified simvastatin dimer content which is reproducible.

1 . A process for preparing simvastatin with a specified simvastatin dimer content, comprising the steps of: 
 a) lactonizing an ammonium salt of simvastatin in aromatic hydrocarbon at a concentration of less than about 60 g/l to form a simvastatin;    b) dissolving the simvastatin in at least one solvent selected from the group consisting of toluene, ethylacetate, tetrahydrofuran, and benzene and precipitating the dissolved simvastatin with an anti-solvent selected from the group consisting of pentane, hexane, heptane, cyclohexane and petroleum ether;    c) isolating the crystallized simvastatin;    d) dissolving the crystallized simvastatin in at least one solvent selected from the group consisting of toluene, ethylacetate, tetrahydrofuran, and benzene and precipitating the dissolved simvastatin with an anti-solvent selected from the group consisting of pentane, hexane, heptane, cyclohexane and petroleum ether;    e) isolating the recrystallized simvastatin;    f) dissolving the simvastatin obtained in step e) in a water miscible organic solvent selected from the group consisting of methanol, ethanol, acetone, acetonitrile and tetrahydrofuran; and    g) adding an anti-solvent to induce precipitation to obtain recrystallized simvastatin,    wherein the recrystallized simvastatin contains a simvastatin dimer content of less than 0.2% wt.    
   
   
       2 . The process of  claim 1 , wherein the steps f-g) are repeated.  
   
   
       3 . The process of  claim 1 , wherein the water miscible organic solvent is methanol.  
   
   
       4 . The process of  claim 1 , wherein the anti-solvent is water.  
   
   
       5 . A process for preparing simvastatin with a specified simvastatin dimer content, comprising the steps of: 
 a) lactonizing an ammonium salt of simvastatin in toluene at a concentration of less than about 60 g/l to form a simvastatin;    b) dissolving the simvastatin in toluene and precipitating the dissolved simvastatin with hexane;    c) isolating the crystallized simvastatin;    d) dissolving the crystallized simvastatin in toluene and precipitating the dissolved simvastatin with hexane;    e) isolating the recrystallized simvastatin;    f) dissolving the simvastatin obtained in step e) in methanol; and    g) adding water to induce precipitation to obtain recrystallized simvastatin,    wherein the recrystallized simvastatin contains a simvastatin dimer content of less than 0.2% wt.