合成路线1

Drospirenone can been obtained by different ways: 1) Fermentation of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) with Botryodiplodia malorum gives the corresponding 7beta-hydroxy derivative (II), which is regioselectively acylated with pivaloyl anhydride and DMAP in pyridine to yield the 3beta-pivaloyloxy steroid (III). The epoxidation of (III) with tert-butylhydroperoxide catalyzed by VO(acetonylacetonate)2 complex affords the corresponding epoxide (IV), which is treated with PPh3 and CCl4 in dichloromethane to provide the 7alpha-chloro derivative (V). Reaction of (V) with Zn in AcOH/THF gives 5beta-hydroxy-3beta-(pivaloyloxy)-15beta,16beta-methylene-6-androsten-17-one (VI), which is hydrolyzed with KOH and NaClO4 in methanol/THF to provide 3beta,5beta-dihydroxy-15beta,16beta-methylene-6-androsten-17-one (VII). The cyclopropanation of (VII) with diiodomethane and Zn in hot ethylene glycol dimethylether gives 3beta,5beta-dihydroxy-6beta,7beta:15beta,16beta-dimethyleneandrostan-17-one (VIII), which is condensed with propargyl alcohol (IX) by means of EtOK in THF, yielding 17alpha-(3-hydroxy-1-propynyl)-6beta,7beta:15beta,16beta-dimethyleneandrostan-3beta,5beta,17beta-triol (X). The hydrogenation of (X) with H2 over either Pd/C in THF/methanol/pyridine (1) or Pd/CaCO3 in THF/2-propanol affords the corresponding 17alpha-(3-hydroxypropyl) derivative (XI), which is finally oxidized, lactonized and dehydrated by means of CrO3 in hot pyridine/water. Similar synthetic pathways have been described replacing the pivaloyl-protecting group with either tert-butyldimethylsilyl (TBDMS), dimethyl(3-methylbutyl)silyl or tribenzylsilyl groups: 2) Alternatively, the 17alpha-(3-hydroxypropyl) derivative (XI) can be oxidized with RuCl3 and NaBrO3 in hot acetonitrile/water to give the 3-hydroxyspirolactone (XII), which is finally dehydrated by means of TsOH in THF.