合成路线:The reaction of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) with 1-bromo-3,3 dimethoxypropane (II) by means of Li in THF gives the corresponding 3,3-dimethoxypropyl derivative (III),which by cyclization with acetic acid is converted to the lactol (IV).Oxidation of (IV) with cyclohexanone and aluminum isopropoxide in refluxing toluene yields 15beta,16beta-methylene-4-androstene[17(beta-1')-spiro)-5']perhydrofuran-2',3-dione (V),which is dehydrogenated with chloranil in refluxing tert-butanol to the 4,6-androstadiene (VI).Cyclopropanation of (VI) with trimethylsolfoxoniurn iodide (A) and NaH in DMSO affords the 6beta,7beta:15beta,16beta-dimethylene compound (VII),which is finally dehydrogenated by means of 2,3-dichloro-5,6-dicyanobenzoquinone in refluxing dioxane.
参考文献标题:6beta,7beta;15,16-Dimethylene-1,4-androstadien-3-ones,their preparation and use as medicinal agents
文献作者:Wiechert,R.; et al.(Schering AG)
参考来源:DE 2922500; EP 0019690; JP 55162799
合成路线:The reaction of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) with 1-bromo-3,3 dimethoxypropane (II) by means of Li in THF gives the corresponding 3,3-dimethoxypropyl derivative (III),which by cyclization with acetic acid is converted to the lactol (IV).Oxidation of (IV) with cyclohexanone and aluminum isopropoxide in refluxing toluene yields 15beta,16beta-methylene-4-androstene[17(beta-1')-spiro)-5']perhydrofuran-2',3-dione (V),which is dehydrogenated with chloranil in refluxing tert-butanol to the 4,6-androstadiene (VI).Cyclopropanation of (VI) with trimethylsolfoxoniurn iodide (A) and NaH in DMSO affords the 6beta,7beta:15beta,16beta-dimethylene compound (VII),which is finally dehydrogenated by means of 2,3-dichloro-5,6-dicyanobenzoquinone in refluxing dioxane.
合成路线:Starting compound (I) is hydroxylated microbiologically by means of Botryodiplodia malorum to 3,7-dihydroxy-15beta,16beta-methylene-5-androsten-17-one (VIII),which is selectively acylated with pivalic anhydride to the monoacyl derivative (IX).Epoxidation of (IX) with tert-butyl hydroperoxide in hot toluene yields the epoxide (X),which by reaction with triphenylphosphine and CCl4 is converted to the chloroepoxide (Xl).The reactive elimination of Cl with Zn-acetic acid followed by hydrolysis with KOH yields 3,5-dihydroxy-15beta,16beta-methylene-6-androsten-17-one (XII),which is submitted to cyclopropanation with methyrene iodide and Zn/Cu in glyme yielding 3,5-dihydroxy-6beta,7beta:15beta,16beta-dimethyleneandrostan-17-one (XIII).The reaction of (XIII) with propargyl alcohol (XIV) by means of potassium ethoxide in THF affords the 17-(3-hydroxy-1-propyn-1-yl) derivative (XV),which is reduced with H2 over Pd/CaCO3 in THF to the corresponding 3-hydroxypropyl derivative (XVI).Finally,this compound is oxidized and cyclized by means of pyridinium dichromate to (VII) ),which is finally dehydrogenated by means of 2,3-dichloro-5,6-dicyanohenzoquinone in refluxing dioxane.
合成路线:3beta-Hydroxy-5-androsten-17-one (XVII) is dihydroxylated microbiologically by means of Colletotrichum lini to 3beta,7alpha,15alpha-trihydroxy-5-androsten-17-one (XVIII),which is treated with acetone and boron trifluoride etherate yielding the acetonide (XIX).Hydrolysis of (XIX) with HCl in methanol affords the 3beta,7beta,15alpha-isomer (XX),which is also obtained from (XVIII) by isomerization with perchloric acid in methylisobutylketone.Selective acylation of (XX) with pivaloyl chloride affords the 3beta,15alpha-dipivaloyloxy compound (XXI),which is submitted to cyclopropanation with trimethylsulfoxonium iodide and NaOH as before yielding (IX).
参考文献标题:Spirorenone
文献作者:Serradell,M.N.; Robinson,C.P.; Castar,J.
参考来源:Drugs Fut 1985,10(6),478
合成路线:The reaction of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) with 1-bromo-3,3 dimethoxypropane (II) by means of Li in THF gives the corresponding 3,3-dimethoxypropyl derivative (III),which by cyclization with acetic acid is converted to the lactol (IV).Oxidation of (IV) with cyclohexanone and aluminum isopropoxide in refluxing toluene yields 15beta,16beta-methylene-4-androstene[17(beta-1')-spiro)-5']perhydrofuran-2',3-dione (V),which is dehydrogenated with chloranil in refluxing tert-butanol to the 4,6-androstadiene (VI).Cyclopropanation of (VI) with trimethylsolfoxoniurn iodide (A) and NaH in DMSO affords the 6beta,7beta:15beta,16beta-dimethylene compound (VII),which is finally dehydrogenated by means of 2,3-dichloro-5,6-dicyanobenzoquinone in refluxing dioxane.
参考文献标题:A new synthesis for aldosterone-antagonistic spirorenone
文献作者:Petzoldt,K.; Wiechert,R.; Laurent,H.
参考来源:Angew Chem 1983,95(5),413-414
合成路线:Starting compound (I) is hydroxylated microbiologically by means of Botryodiplodia malorum to 3,7-dihydroxy-15beta,16beta-methylene-5-androsten-17-one (VIII),which is selectively acylated with pivalic anhydride to the monoacyl derivative (IX).Epoxidation of (IX) with tert-butyl hydroperoxide in hot toluene yields the epoxide (X),which by reaction with triphenylphosphine and CCl4 is converted to the chloroepoxide (Xl).The reactive elimination of Cl with Zn-acetic acid followed by hydrolysis with KOH yields 3,5-dihydroxy-15beta,16beta-methylene-6-androsten-17-one (XII),which is submitted to cyclopropanation with methyrene iodide and Zn/Cu in glyme yielding 3,5-dihydroxy-6beta,7beta:15beta,16beta-dimethyleneandrostan-17-one (XIII).The reaction of (XIII) with propargyl alcohol (XIV) by means of potassium ethoxide in THF affords the 17-(3-hydroxy-1-propyn-1-yl) derivative (XV),which is reduced with H2 over Pd/CaCO3 in THF to the corresponding 3-hydroxypropyl derivative (XVI).Finally,this compound is oxidized and cyclized by means of pyridinium dichromate to (VII) ),which is finally dehydrogenated by means of 2,3-dichloro-5,6-dicyanohenzoquinone in refluxing dioxane.
参考文献标题:Synthesis of spirorenone.A novel highly active aldosterone antagonist
文献作者:Laurent,H.; Hormeister,H.; Nickisch,K.; Butler,D.; Nickolson,R.; Wischert,R.; Petzoldt,K.
参考来源:Angew Chem 1982,94718
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