16-SUBSTITUTED STEROIDS

Estriol was originally obtained (1930) by isolation from human pregnancy urine by Marrian (1) and by Doisy et al. (2).Both Doisy (2) and Marrian (3) showed that estriol differed from estrone, another estrogenic hormone occurring in gravid urine, in possessing three acetylizable hydroxyl groups instead of the one hydroxyl and one carbonyl.Butenandt (4) soon (1931) proved that estriol might be regarded empirically as the hydrate of estrone by demonstrating tha.t the trihydroxy estrogen could be dehydrated to produce the ketonic estrogen with the elimination of 1 molecule of water.These findings, therefore, indicated that two of the hydroxyl groups in estriol were vicinal in position and that one of these vi&al hydroxyl groups occupied the same position on the steroid nucleus as that of the carbonyl in estrone.Later researches (5), in which many investigators contributed significant work, served to elucidate fully the correct structural formulas of estrone (I) and estriol (VI).Estriol was first prepared from estrone by the author (6) in 1944.It is now possible to obtain it in over-all yields in the neighborhood of 25 per cent.Exact details for the method are described in this publication.In general, estrone (I) is methylated (7) to produce the 3-methyl ether (II), and the lat,ter is nitrosated (8) to give the 16-oximino derivative (III).The 16-oximino compound is next carried through a Stodola reduction (9), and from this reaction there is obtained a crude a-ketol (IV) which may be either directly submitted to further reduction or else first purified and then reduced to the a-glycol.The reduction to the final carbinol state with pure cu-ketol results in a mixture of two isomeric ar-glycols; however, from this mixture estriol 3-methyl ether (V) may be easily obtained by fractional crystallization.The synthetic estriol 3-methyl ether is then acetylated, demethylated, and finally saponified to produce estriol (VI) itself.In this synthesis the salient feature is the use of sodium amalgam in dilute ethanolic acetic acid (temperature 40") as the agent for transforming t.he a-ketol to the cy-glycol.Reduction of the or-ketol with hydrogen in the presence of a catalyst has always, in our hands, given rise to an isomer (10)