Compounds related to the steroid hormones. Part XVII. An improved method of preparation of 21-acetoxy-17-hydroxy-16β-methyl-5α-pregn-9-ene-3,20-dione

Abstract

3β-Acetoxy-16α,17α-epoxy-16β-methyl-5α-pregn-9-en-20-one and the corresponding alcohol are rearranged by mineral acids to the 17α-hydroxy-16-methylene- or the 17α-hydroxy-16-methyl-Δ¹⁵-compounds, depending upon the reaction medium. The 16-methylene compound is reduced predominantly to the 16β-methyl isomer in presence of platinum in neutral solvents; palladium and rhodium catalysts produce mixtures of the 16-methyl epimers. The 17α-hydroxy-16-methyl-Δ¹⁵-compound is more prone than its 16-methylene isomer to produce the 16α-methyl compound on hydrogenation.

Improved stereospecificity of reduction is possible if a 21-acetoxy-group is introduced beforehand. This can be efficiently done by treating 3β,17-dihydroxy-16-methylene-5α-pregn-9-en-20-one with bromine in ethanolic hydrogen chloride and subsequent acetolysis; some other applications of this method of bromination are described. Reduction of 21-acetoxy-3β,17-dihydroxy-16-methylene-5α-pregn-9-en-20-one with platinum catalysts gives the corresponding 16β-methyl compound, accompanied by little of the 16α-epimer; even greater stereospecificity results from use of iridium catalysts.

These methods, together with an improved oxidation of the 3β-hydroxy-group, have allowed the preparation of 21-acetoxy-17-hydroxy-16β-methyl-5α-pregn-9-ene-3,20-dione in 76% overall yield from 3β-acetoxy-16-methyl-5α-pregna-9,16-dien-20-one.