The Synthesis of 17α-Methyl-11β-arylestradiol:  Large-Scale Application of the Cerium (III)-Mediated Alkylation of a Ketone

Abstract

17α-Methyl-11β-arylestradiol (17α-methyl-11β-(4-(2-(1-piperidinyl)ethoxy)phenyl)estra-1,3,5(10)-triene-3,17β-diol) is a new molecule developed by Aventis Pharma for the treatment of osteoporosis. It was produced on the pilot plant scale from the norsteroid intermediate ethylene deltenone (3,3-ethylenedioxyestra-5(10)-9(11)-diene-17-one). Stereoselective epoxidation of the 5(10)-olefin was performed by hydrogen peroxide and hexachloroacetone, the most selective of the systems tested. The 11β-aryl appendage was introduced as a cuprate generated catalytically from the related Grignard reagent. The A-ring was aromatized by a mixture of acetyl bromide and acetic anhydride. This reaction was optimized by a Design Of Experiments carried out on an automated workstation. The advantages and limits of this approach are discussed. The last step consisted of the stereospecific alkylation of the 17-ketone by methylmagnesium bromide and dehydrated cerium trichloride. The drug substance was crystallized as a hydrate (overall yield = 23%).