Synthesis And Characterization Of Aromatic Esters Based On3β,5α-Dihydroxy-16-Pregnene-6,20-Dione Skeleton

With the important steroid drug intermediate16-dehydropregnenolone acetate (16-DPA) which is relatively cheap and easily available as the starting material, a series of new aromatic esters based on3β,5α-dihydroxy-16-pregnene-6,20-dione skeleton were synthesized through four steps consisting of epoxidation, ring opening, hydrolysis and esterification. These target compounds may show potential biological activities in the fields of inhibitor of5α-reductase, antiandrogenic agent, antioxidant, lower blood lipid and so on, and could be also used for the biological screening. The chemical structures of the steroidal products were characterized by1H NMR,13C NMR, IR and mass spectrum. The following research contents are contained in this dissertation:1. With16-DPA as the starting material, a series of16-DPA derivatives—3β,5α-dihydroxy-16-pregnene-6,20-dione aromatic formic acid ester were obtained by a four-step synthetic route including epoxidation of C5-double bond, ring opening, hydrolysis of C3-acetyl, and the subsequent esterification. These products may be used for the biological evaluation.For the C3-acetyl hydrolysis reaction to produce3β,5α-dihydroxy-16-pregnene-6,20-dione, the reaction conditions were altered by using potassium hydroxide/methanol system to replace sodium hydroxide/t-BuOH and the yield was improved.2. It was found that the esterification reaction between3β,5α-dihydroxy-16-pregnene-6,20-dione and an aromatic formic acid in the presence of N,N’-dicyclohexylcarbodiimide (DCC) and4-dimethylaminopyridine (DMAP) was regioselective. Esterification reaction at the5-hydroxy group of the substrate3(3,5a-dihydroxy-16-pregnene-6,20-dione could not proceed because of the large steric hindrance and the hydrogen bonding between the5-hydroxy and adjacent carbonyl groups. The esterification reaction took place at the3-hydroxy group and the yields of the esters were44%-98%. The esterification is a kind of nucleophilic substitution. Strong electropositivity of the carbonyl carbon and small steric hindrance in the substrate3(3,5a-dihydroxy-16-pregnene-6,20-dione were beneficial to the esterification reaction. The esterification reaction between the substrate and aromatic acids with electron-withdrawing groups and small steric hindrance, e.g.3,4-dichlorobenzoic acid and4-fluorobenzoic acid afforded high yields of98%and94%, respectively. While the reaction between the substrate and an aromatic acid with an electron-donating group, e.g.2-methoxybenzoic acid gave a low yield of44%.3. Characterization of the serial derivatives. The chemical structures of the synthesized3(3,5a-dihydroxy-16-pregnene-6,20-dione-3-aromatic eater products were characterized by IR,1H NMR,13C NMR and LC-MS.