Crystal Structure and Synthesis of <i>N</i>-cyclohexyl-3<i>β</i>-hydroxyandrost-5,16-diene-17-carboxamide dihydrate

Abstract

The 5a-Reductase (5aR) [EC 1.3.99.5] has an important enzymatic role in amplifying the androgenic response at prostatic tissues. It catalyzes the NADPH-dependent reduction of testosterone into 5a-dihydrotestosterone (5a-DHT) which, in turn, is responsible for the development of prostatic pathologies, such as Benign Prostatic Hyperplasia (BPH) and Prostate Cancer (PC).1 According to World Health Organization, PC is most prevalent in a mature male,2 whereas BPH is the second leading cause of prostatic surgeries,3 making such conditions to be public health problems. Due to the biological role of 5aR in the development of BPH and CP, its inhibition is a strategic target for rational drug design. Continuing our research on 5aR inhibitors, in the present paper the synthesis and X-ray structure determination of a novel steroidal 17-N-cyclohexylcarboxamide are described. The title compound, N-cyclohexyl-3b-hydroxyandrost-5,16diene-17-carboxamide, was prepared from commercially available 16-dehydropregnenolone acetate. This compound was submitted to the bromoform reaction to yield carboxylic acid, whose alcohol in C3 was protected by acetylation to produce the ester. In order to form the 17-N-cyclohexylcarboxamide moiety it was necessary to originate in situ an acyl chloride derivative, which in turn reacted with cyclohexylamine. Finally, the alcohol in C3 (100 mg, 23 mmol dissolved in hot MeOH, 20 mL) was removed by basic hydrolysis (a 2% aqueous sodium hydroxide solution, 7 mL) to yield the N-cyclohexyl-3bhydroxyandrost-5,16-diene-17-carboxamide. The crude product was purified by silica-gel column chromatography (hexane:ethyl acetate, 7:3); yield, 80% of pure product. Crystals suitable for X-ray Structure Analysis Online