Abstract

The present disclosure provides novel intermediates trimethylsilyl protected aralkyl amide of lovastatin and trimethylsilyl protected Simvastatin aralkyl amide. It further provides a process for the preparation of these intermediates and their conversion to Simvastatin.

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            Simvastatin, a HMG-CoA reductase inhibitor, is chemically butanoic acid, 2,2-dimethyl-1, 2, 3, 7, 8, 8a-hexahydro-3, 7-dimethyl-8- [2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1a, 3a, 7b, 8b (2S^*, 4S^*), -8ab]] and is known from U.S. Pat. No. 4,444,784. Simvastatin is represented by Formula VIII.

U.S. Patent No. 4,444,784 discloses a process for the preparation of Simvastatin, which involves indirect methylation of the C-8 side chain of lovastatin through several chemical steps: deesterification of the whole 2-methylbutyrate side chain, protection of the pyranone ring 4-hydroxy group with a tert-butyldimethylsilyl protective group, reesterification of the protected lactone with 2,2-dimethylbutyric acid, and deprotection of the pyranone ring hydroxy group. This procedure involves multiple chemical reactions with a low overall yield.

U.S. Patent No. 4,582,915 discloses a process for the preparation of Simvastatin, wherein alkali metal salt of lovastatin is alkylated with methyl halide and an alkali metal amide, followed by acidification and lactonization. This process involves low yield and increased impurity formation as different sites of the molecule are methylated.

U.S. Patent No. 4,845,237 discloses a process for the preparation of Simvastatin, wherein acyl chloride is activated by an alkali metal bromide more specifically lithium bromide and 4-dialkylaminopyridine, which is further used for acylation of silyl protected diol lactone. This process involves special treatment of lithium bromide such as drying at high temperature at 135° C for three days under vacuum condition and stored in dried condition as it is hygroscopic in nature. If the wet lithium bromide is used, the yield is lower due to the formation of the by-product.

U.S. Patent No. 4,820,850 discloses a process for the preparation of Simvastatin, wherein

tert-butyldimethylsilyl protected lovastatin alkyl amide is alkylated with alkyl halide and alkyl metal amide followed by deprotection of silyl group, hydrolysis of alkyl amide group and lactonization. The process utilizes a highly expensive silylating agent, tert-butyldimethylsilyl chloride, to protect the hydroxyl groups and lactonization at high temperature leads to product degradation thus rendering the process cost ineffective.

U.S. Patent No. 5,159,104 discloses a process for th...