A New Method for the Synthesis of Antihypercholesterolemic Agent Simvastatin

Abstract

A new synthetic method for the preparation of the cholesterol-lowering drug simvastatin from the naturally occurring lovastatin is reported. The synthesis employs first the protection of the OH group of lovastatin (1) and then the protection of the lactone CO group to prevent enolization via conversion to the orthoesters 4a and 4b. Alkylation of the 2-methylbutyrate side chain is then successfully achieved. Removal of the protecting groups affords antihypercholesterolemic agent simvastatin (2).Introduction. ± Simvastatin (2), like other statins (lovastatin (1), pravastatin, mevastatin, atorvastatin, fluvastatin, cervastatin, etc., derivatives and analogs thereof) is a (hydroxymethyl)glutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor and is used as an antihypercholesterolemic agent [1 ± 5].