Phosphonic acids—IX : Steroidal 21a-phosphonate esters

Abstract

Dialkyl esters of steroidal 21a-phosphonic acids, which may be regarded as phosphonate analogs of 21-phosphate esters with the oxygen link replaced by a methylene group, were synthesized by the reaction of a trialkyl phosphite with a quarternary salt of a Mannich base derivative of a 20-keto steroid. In this way, the 21-dialkoxyphosphinylmethyl group, (RO) 2P(O)CH 2—, was introduced into pregnenolone, 17α-hydroxypregnenolone and 17α-acetoxypregnenolene, and the products converted by oxidation to the corresponding progesterone derivatives. The same steroid phosphonates also were obtained by the reaction of alcoholic trialkyl phosphite with the 20-keto-Δ 21(21a)-steroid formed by thermal decomposition of the Mannich base salt. Monodealkylation of the 21a-dialkyl phosphonate esters to furnish the corresponding monobasic acids was effected smoothly by warming with alcoholic sodium propylmercaptide, except in the case of 17α-acetoxy-20-ketosteroids where this reagent caused a condensation between the acetoxy group and the side chain accompanied by d-homoannulation. Although the reaction of 21-iodoprogesterone with triethyl phosphite or sodium diethylphosphonate gave only progesterone, 21-tosyloxyprogesterone reacted with triethyl phosphite to yield 21-diethoxyphosphinylprogesterone.