Eugene P. Oliveto

The photochemical rearrangement of steroidal 17-nitrites

Abstract The photolysis, in solution, of steroidal 17-nitrile esters gives rise to the 17a-aza- D -homo-17a-ol 17-one system. This hydroxamic acid grouping is considered to arise via carbon-carbon fission of an intermediary alkoxy radical. The isolation, from one and the same photolysis mixture, of two isomeric hydroxamic acids shown to be epimeric at C-13 supports the proposal of ring fission between C-13 and C-17.

SYNTHESIS OF 16α‐ AND 16β‐METHYL CORTICOIDS

The search for better corticoids involves, for the most part, introduction of functional groups into known anti-inflammatory steroids in the hope of diminishing or eliminating the unwanted and undesirable effects that have no bearing on the anti-inflammatory action. A secondary aim is to increase potency, but this is justified only if there is no corresponding increase in side effects, so that the ultimate aim is really the same: namely, separation of responses and an increase in the therapeutic ratio. Despite attempts to inject some rationale into corticoid research, there is still more art than science in deciding which functional groups to introduce and at what point in the molecule to place them. There are by now many examples of corticoids that have been modified by the addition of a methyl group at various points in the molecule^.^-^ These added groups have had unpredictable and variable effects on the activity of the parent corticoid, ranging from complete loss of activity to a marked increase in saltand water-retaining effects. Thus, there was no way of knowing in advance what the properties of 16-methyl-substituted corticoids would be. Actually, the key reactions for introduction of methyl groups at C-16 had been discovered in 1942 by Marker and Crooks6 for 16a-methyl (FIGURE 1) and, in 1944, by Wettstein’ for 168-methyl (FIGURE 2). With this pioneer work as a background, the next logical step toward the preparation of 16-methyl corticoids is choice of the proper starting steroid. It is an interesting side light that both Merck* and Schering used not only the same raw material but also, essentially, the same synthesis for the preparation of both 16a-methylprednisone and 16@-methylprednisone.8-’0 The raw material is desoxycholic acid, which is converted to 3a-acetoxypregnane-ll , 20dione in about a 15-step synthesis. A AlS double bond is then introduced, either by direct bromination-dehydrobromination, or by first preparing the enol acetate and following with brominating-dehydrobrominating (FIGURE 3). The 168-methyl group can then be introduced by the Wettstein procedure (FIGURE 4) and the remainder of the synthesis to 168-methylprednisone completed by standard procedures: (1) introduction of the 17a-hydroxy by enol acetylation, peroxidation, and hydrolysis; (2) introduction of the 21-acetoxyl by bromination, followed by reaction with potassium acetate; (3) oxidation of the 3-hydroxyl to ketone with chromium trioxide or N-bromosuccinimide; and (4) dibromination at C-2 and C-4, followed by dehydrobromination with collidine or dimethylformamide to produce 168-methylprednisone acetate. The 21-acetate may then be hydrolyzed to alcohol with either acid or alkali, to yield 168-methylprednisone (FIGURES 5 and 6). To prepare the 9a-halo analogues, an intermediate from the above synthesis, 168-methyl-3a, 17a-dihydroxypregnane-ll , 20-dione, is reacted with ethylene glycol and an acid catalyst to form a 20-monoethylene ketal, the 11-ketone is

The synthesis of 6α,16α- and 6α,16β-dimethyl-9α, 11β-dichlobo-1,4-pregnadiene-1α,21-diol-5,20-diones

Abstract Synthetic schemes leading to the title compounds (XII and XXII) from 6,16-dimethyl-5,16-pregnadien-5β-ol-20-one acetate are described.