Dihydrocortisone

Many anti itch remedies contain dihydrocortisone... 

The bromination of 4,5-j -dihydrocortisone acetate in buffered acetic acid does not proceed very cleanly (<70%) and, in an attempt to improve this step in the cortisone synthesis, Holysz ° investigated the use of dimethylformamide (DMF) as a solvent for bromination. Improved yields were obtained (although in retrospect the homogeneity and structural assignments of some products seem questionable.) It was also observed that the combination of certain metal halides, particularly lithium chloride and bromide in hot DMF was specially effective in dehydrobromination of 4-bromodihydrocortisone acetate. Other amide solvents such as dimethylacetamide (DMA) and A-formylpiperidine can be used in place of DMF. It became apparent later that this method of dehydrobromination is also prone to produce isomeric unsaturated ketones. When applied to 2,4-dibromo-3-ketones, a substantial amount of the A -isomer is formed. 

This enzyme [EC 1.3.1.3] catalyzes the reversible reaction of 4,5-/3-dihydrocortisone with NADP+ to produce cortisone and NADPH. 

Prednisone Prednisone is 17a,21-dihydroxypregna-l,4-dien-3,ll-20-trione (27.1.31). Prednisone differs from cortisone in the presence of an additional double bond between Cj and C2. There are various ways of synthesizing it. In one of these, as is in the case when synthesizing cortisone, it is synthesized from dihydrocortisone acetate. However, in the given example, this compound undergoes dibromination by molecular bromine, giving... 

Reductive cleavage of 2,4-dinitrophenylhydrazones. Certain 2,4-dinitrophenyl> hydrazones of 3-ketosteroids can be cleaved under mild conditions if the nitro groups are reduced to amino groups by chromous chloride. Thus when the 2,4-DNP of 4,5a-dihydrocortisone 21-acetate in methylene chloride was shaken in a separatory funnel with chromous chloride and dilute hydrochloric acid for 15 min., workup of the organic layer afforded the ketone in 94% yield. Use of a water-immiscible solvent protects the released ketone an inert atmosphere if required can be provided with dry ice. Cortisone 2,4-DNP was cleaved in only 3-5 hrs. and the yield was 60%. DN P derivatives of A -diene-S-ones were completely resistant to hydrolysis. Contributed by Leon Mandell... 

Extracted metabolites, cortisone, dihydrocortisol, dihydrocortisone, hydrocortisone... 

This functionalization has been used for a synthesis of cortisone from cor-texolone that is an attractive alternative to biological hydroxylation. Thus irradiation of (5) and lodobenzene dichloride gives, after dehydrohalogenation and saponification, the unsaturated alcohol (6). Hydroboration, oxidation, and deprotection of (6) affords dihydrocortisone, which had been converted previously into cortisone acetate and prednisolone acetate. 

In 1948, Edward C. Kendall, who clarified steroid structures during the 1930s (see chapter 4), and Philip S. Hench (1896-1965), at the Mayo Clinic, demonstrated that the steroid hormone cortisone relieves symptoms of rheumatoid arthritis. Kendall, Hench, and Tadeus Reichstein would share the 1950 Nobel Prize in physiology or medicine. Although Lewis Sarett (1917-99) at Merck had accomplished a total synthesis of cortisone in 1944 (Woodward published a more elegant one in 1951), cortisone and its close derivatives would have remained extremely expensive were it not for the efforts of Percy L. Julian (1899-1975). As soon as he learned of the Mayo Clinic discovery, Julian developed a rapid, inexpensive synthesis of Reichstein s Substance S, also isolated ftom the adrenal cortex. This steroid is easily converted to dihydrocortisone and Julian s pathway remains today the major commercial route to this over-the-counter topical remedy for sunburn, mosquito bites, and other uncomfortable skin irritations. 

The subsequent stages from pregnan-3a-ol-ll,20-dione acetate (I) to cortisone have been recorded by Kritchevsky et al. (1952) (Fig. 4). The enol acetate (II) of I upon treatment with perbenzoic acid forms the epoxide (III), which without isolation is hydrolyzed directly to pregnane-3a,17 -diol-ll,20-dione (IV). Bromination at C-21 (V) and mild treatment with alkali produces the 21-hydroxy derivative (VI), which is oxidized with N-bromoacetamide to dihydrocortisone (VII). Bromination (at C-4) of the 21-acetate of VII followed by dehydrobromination with semi-carbazide leads to the semicarbazone of cortisone acetate (VIII), which can be cleaved in a facile manner with pyruvic acid to cortisone acetate. Under suitable conditions, it is possible to accomplish the oxidation at C-3 and bromination of the ketone at C-4 in one step by means of N-bromoacetamide (Hershberg, Gerold, and Oliveto, 1952b). This synthesis of cortisone acetate from desoxycholic acid outlined in Figs. 3 and 4 is one of the most efficient bile acid processes, since it does not suffer from the difficulties outlined under Section II.2. 

Remote or Inactive Positions.—Breslow and his co-workers have sought to mimic some aspects of enzyme behaviour in other ways, and have published a full paper on remote halogenation of steroids, giving various partial syntheses [e.g. cortexolone (24) to dihydrocortisone (25)] they have extended the principle to remote epoxida-tion. The reiterative functionalization process of Watt has also been applied in the steroid field, providing activation at C-18, and aimed eventually at preparing aldosterone. 

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