Processes for the preparation of simvastatin

A process for the preparation of simvastatin and pharmaceutically acceptable salts thereof comprising the steps of:

• (a) providing a carboxylic acid amine salt of formula I
• wherein R1 and R2 may be the same or different and can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, with the proviso that only one of R1 and R2 can be hydrogen, or R1 and R2 together with the nitrogen atom to which they are bonded are joined together to form a heterocyclic ring;
• (b) lithiating the carboxylic acid amine salt (I) under suitable conditions to form the corresponding 2,2-dimethylbutyrate intermediate of formula IIa
• wherein R1 and R2 have the aforestated meanings;
• and
• (c) lactonizing the 2,2-dimethylbutyrate intermediate (IIa) to provide simvastatin of formula IV:

A process for the preparation of simvastatin and pharmaceutically acceptable salts thereof comprising the steps of:

• (a) providing a carboxylic acid amine salt of formula I
• wherein R1 and R2 may be the same or different and can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, with the proviso that only one of R1 and R2 can be hydrogen, or R1 and R2 together with the nitrogen atom to which they are bonded are joined together to form a heterocyclic ring;
• (b) lithiating the carboxylic acid amine salt (I) under suitable conditions to form the corresponding 2,2-dimethylbutyrate intermediate of formula IIa
• wherein R1 and R2 have the aforestated meanings;
• and
• (c) converting the 2,2-dimethylbutyrate intermediate (IIa) to an ammonium salt of the 2,2-dimethylbutyrate intermediate of formula (IIb):
• (d) lactonizing the ammonium salt of the 2,2-dimethylbutyrate intermediate to provide simvastatin of formula IV:

A process for the preparation of simvastatin and pharmaceutically acceptable salts thereof comprising the steps of:

• (a) providing a carboxylic acid amine salt of formula I
• wherein R1 and R2 may be the same or different and can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, with the proviso that only one of R1 and R2 can be hydrogen, or R1 and R2 together with the nitrogen atom to which they are bonded are joined together to form a heterocyclic ring;
• (b) lithiating the carboxylic acid amine salt (I) under suitable conditions to form the corresponding 2,2-dimethylbutyrate intermediate of formula IIa
• wherein R1 and R2 have the aforestated meanings;
• and
• (c) converting the 2,2-dimethylbutyrate intermediate (IIa) to the corresponding free carboxylic acid;
• and
• (d) lactonizing the free carboxylic acid intermediate to provide simvastatin of formula IV: