16a-hydroxy-hydrocortisone

To 6a-fluoro-16a-hydroxy-hydrocortisone 21-acetate, described by Mills et al, J. Am. Chem. Soc., volume 81, pages 1264 to 1265, March 5, 1959, there was added acetic anhydride in dry pyridine. The reaction mixture was left at room temperature overnight and was then poured with stirring into ice water. The resulting precipitate was filtered, washed with water and crystallized from acetone-hexane to give 6a-fluoro-16a-hydroxy-hydrocortisone-16a,21-diacetate. This was reacted with methane-sulfonyl chloride in dimethyl formamide in the presence of pyridine at 80°C for 1 hour. The mixture was cooled, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the ethyl acetate was evaporated. By recrystallization of the residue from acetone-hexane there was obtained 6a-fluoro-A <" -pregnadiene-16o ,17a,21-triol-3,20-dione 16a,21 diacetate. 

A mixture of 1.2 grams of 6o -fluoro-16a-hydroxy-hydrocortisone, 4 cc of acetic anhydride and 8 cc of pyridine was heated at 60°C for 2 hours and then kept at room temperature for 2 hours. Ice and water were added and the solid was collected, washed with water, dried and recrystallized from methylene chloride-methanol, thus giving 1.05 grams of the... 

To 6a-fluoro-16a-hydroxy-hydrocortisone 21-acetate, described by Mills et al,... 

A mixture of 1.38 grams of the above compound and 15 cc of dioxane was treated with 1.9 cc of a 0.5 N aqueous solution of perchloric acid and 600 mg of N-bromoacetamide, adding the latter in the dark, in three portions, in the course of half an hour and under continuous stirring, It was then stirred for a further 1% hours in the dark, then the excess of reagent was decomposed by the addition of aqueous sodium bisulfite solution and ice water was added the product was extracted with methylene chloride, washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure, thus giving a yellow oil consisting of the 16,21-diacetate of 6a-fluoro-9a-bromo-16a-hydroxy-hydrocortisone which was used for the next step without further purification. 

A mixture of 290 mg of the 16,21-diacetate of 6a,9a-difluoro-16a-hydroxy-hydrocortisone, 30 cc of t-butanol, 0.5 cc of pyridine and 150 mg of selenium dioxide was refluxed for 53 hours under an atmosphere of nitrogen and cooled ethyl acetate was added and filtered through celite the solvent was evaporated to dryness under reduced pressure, the residue was triturated with water, the solid was collected by filtration, washed with water and dried. The product was then chromatographed on 10 grams of silica gel. The solid fractions eluted with acetone-methylene chloride (1 19) were recrystallized from methylene chloride, thus affording 68 mg of the 16,21-diacetate of 6a,9a-difluoro-16a-hydroxy-prednisolone MP 212° to 215°C. 

Biological studies on 16a-hydroxy-hydrocortisone [15] have demonstrated that this type of corticoid derivative still maintains a considerable activity in the usual types of assays (glycogen deposition, thymus involution and anti-inflammatory tests). It was therefore of interest to prepare the 16a-hydroxy derivatives of the more potent 9a-halo steroids. 

I60C-Hydroxy Derivatives of Gorticoids and their Acetonides. The preparation of 16a-hydroxy-9a-fluoroprednisolone (48) from the 3,20-bisethylene ketal of hydrocortisone acetate (49) has been reported (73). The latter was dehydrated with thionyl chloride in pyridine to yield the 4,9(11),16-triene (50). The 16,17-unsaturated linkage was selectively hydroxylated with OsO /pyridine to yield the 16a,17a-diol (51), which was converted... 

Introduction of the 16a-hydroxyl group into 9-fluoro-hydrocortisone and 9-fluoro-prednisolone has been shown by Bernstein et al. [16] to result in complete suppression of the salt-retaining properties of these steroids, without appreciably impairing their glucocorticoid activity. Moreover, studies in man have demonstrated the anti-arthritic activity of 9-fluoro-16a-hydroxy-prednisolone and have confirmed its lack of salt-retaining activity. Subsequently, Lederle reported that the anti-inflammatory potency was lowered, but salt retention was eliminated. 

The introduction of a 16a-hydroxy group into 6a,9-difluoro-prednisolone led to a compound (fluocinolone) with the anticipated favorable biological spectrum, namely high anti-inflammatory activity (35-fold that of hydrocortisone, seven-fold that of triamcinolone) and - in contrast to the C-16 unsubstituted compound - no retention of sodium. The corresponding 16,17-acetonide (fluocinolone acetonide) exhibited 100-fold the anti-inflammatory activity of hydrocortisone, with no sodium retention. In clinical trials, 6a,9-difluoro-16a-hydroxyprednisolone was found to be a potent suppressor of inflammatory conditions such as rheumatoid arthritis, as well as allergic conditions such as asthma, whilst its acetonide proved to be highly effective as topical corticoid. 

---