A Cost-Efficient Synthesis of Simvastatin via High-Conversion Methylation of an Alkoxide Ester Enolate

A cost-efficient synthesis of simvastatin (2), starting from mevinolin (lovastatin) (1a) or its precursor mevinolinic acid (1b), is reported. This synthesis involves the use of a new intermediate, lovastatin cyclopropylamide (3), eliminating two chemical steps of protection and deprotection of the open dihydroxy form of (1a). Synthesis is based on the high-conversion methylation of an alkoxide ester enolate and involves only four chemical steps. Methylation reaction conditions have been optimized to get >99.5% conversion. Process is economical on large-scale and product (2) is obtained in 85% overall yield.