SYNTHESIS OF 17α-Hydroxycorticosterone AND ITS 9α-Halo DERIVATIVES FROM 11-Epi-17α-Hydroxycorticosterone

Selectfluor: Mechanistic Insight and Applications

“…[97] A year earlier, they had described the synthesis of derivatives of the glucocorticoid hydrocortisone (33 a), a steroid hormone with anti-inflammatory and thymolytic activity. Substitution of the 9-aH atom of hydrocortisone acetate for an iodine, bromine, or chlorine atom resulted in an increase in activity relative to that of the natural compound only in the case of the chlorine derivative 33 c. [98] The general trend in this series suggested that the activity was inversely proportional to the size of the halogen substituent, thus prompting the synthesis of the fluorinated derivative. [97] As can be seen in Table 13, 33 b is more than ten times as active as naturally occurring hydrocortisone; more importantly, these studies established fluorination as a promising method for improving the activity of pharmacologically relevant compounds.…”

Elemental fluorine

“…The combined, dried (MgSO 4 ), organic extracts were evaporated to give a pale yellow solid (3.1 g, 41% conv.). 19 F NMR analysis of the crude product showed the presence of three major mono-fluorinated products; d F À162.39 (t, 3 J HF 38.9, 5a-F), À164.09 (ddd, 3 3.4. Reaction of 3b-acetoxy-5a-androstan-17-one with Selectfluor 1 A mixture consisting of 3b-acetoxy-5a-androstan-17-one 1 (300 mg, 0.905 mmol) and freshly distilled anhydrous acetonitrile (20 mL) was placed in the round-bottomed flask.…”

“…Absolute configurations could not be determined for the lack of anomalously scattering atoms and were inferred from those of the precursors. Crystal data for 3b/3c 1 : C 21 H 31 FO 3 …”

“…The sometimes-considerable enhancement of biological activity of steroids by the introduction [1] of a single fluorine atom into the structure was first reported by Fried and Sabo [2] when they compared glucocorticoid activities of 9a-halogeno derivatives of hydrocortisone acetate [3] (Scheme 1). This important early milestone in bio-organic fluorine chemistry prompted not only the synthesis of many fluorinated steroids [4] but numerous fluorinated bioactive compounds which, in turn, led to the launch of an increasing number of commercially very successful pharmaceuticals [5].…”

The crystal and molecular structure of 12α-bromo-11β-hydroxyprogesterone

“…By 9~-or 12~-halogenation [X and Y in (I)], however, activity over a wide range of hormonal and antihormonal effects is achieved, often surpassing progesterone in activity (Fried & Sabo, 1953;Hertz, Fried & Sabo, 1956). The almost equal activities of corresponding 9e-and 120c-halogenation products suggest that the enhancement in activity is a result of increase in acidity of the lift-hydroxyl group, brought about by the inductive effect of the neighboring electrophilic c~ substituent.…”