1) By the reaction of 4-methyl-3-oxo-4-aza-5alpha-androstane-17beta-carboxylic acid (I) with diisopropylcarbodiimide (II) in methylene chloride at room temperature.
2) By the reaction of 3-oxoandrost-4-ene-17beta-carboxylic acid (III) with diisopropylcarbodiimide (II) in refluxing ethyl acetate and subsequent A-ring opening of compound (IV) by treatment with the Lamieux-von Rudloff reagent (permanganate-periodate) in isopropanol. The cyclization of the secoacid (V) so obtained, with methylamine in dioxane under pressure, followed by the hydrogenation under pressure, on 10% Pd/C in ethanol, affords turosteride. This method is used for the large scale production of turosteride.
The synthesis of [14C]-turosteride has been reported: The reaction of 20-[14C]-3-hydroxy-5-pregnen-20-one (I) with iodine and pyridine gives the pyridinium derivative (II), which is treated with sodium methoxide and methanol yielding 3-hydroxy-5-androstene-17beta-carboxylic acid methyl ester (III). The oxidation of (III) with cyclohexanone and aluminum isopropoxide affords 3-oxo-5-androstene-17beta-carboxylic acid methyl ester (IV), which is oxidized with potassium permanganate and sodium periodate to the propionic acid derivative (V). The cyclization of (V) with methylamine in diglyme at 180 C affords 4-methyl-3-oxo-4-aza-5-androstene-17beta-carboxylic acid methyl ester (VI), which is hydrogenated with H2 over PtO2 in acetic acid to the corresponding saturated compound (VII). The saponification of (VII) with KOH in refluxing methanol/water gives the 4-methyl-3-oxo-4-aza-5alpha-androstane-17beta-carboxylic acid (VIII), which is finally condensed with diisopropylcarbodiimide (IX) in refluxing dichloromethane.