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).
合成路线:The acylation of spiro[pregnane-17,2'-tetrahydrofuran]-4,6,15-triene-3,5'-dione (I) with thioacetic acid in refluxing methanol gives the 7-acetylthio derivative (II),which is methylenated with trimethylsulfoxonium iodide and NaH in refluxing DMSO,yielding the 15beta,16beta-methylene derivative (III).Finally,this compound is dehydrogenated with 2,3-dichloro-5,6-dicyanobenzoquinone (IV) in refluxing benzene.
合成路线:3) Reaction of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) with 1-bromo-3,3-dimethoxypropane (XIII) and lithium in THF gives the 17alpha-(3,3-dimethoxypropyl) derivative (XIV),which by treatment with 70% acetic acid provides the spiro compound (XV).Oxidation of compound (XV) with cyclohexanone in the presence of (i-PrO)3Al and then treatment with 2N H2SO4 affords 15beta,16beta-methylene-3-oxo-17alpha-pregn-4-ene-21,17-carbolactone (XVI).Treatment of (XVI) with chloranil in t-BuOH yields the pregnadiene carbolactone (XVII),which is finally reacted with trimethylsulfoxonium iodide (XVIII) and NaH in DMSO.
参考文献标题:Novel spironolactones and process for their preparation
文献作者:Losert,W.; Bittler,D.; Vasals-Stenzel,J.; Wiechert,R.; Kerb,U.(Schering AG)
参考来源:DE 2652761; US 4129564
合成路线: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.
合成路线:This compound has been obtained by different ways:1.The fermentation of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) or 3beta-acetoxy-15beta,16beta-methylene-5-androsten-17-one (II) with Botryodiplodia malorum gives the corresponding 3beta,7beta-dihydroxy derivative (III),which is regioselectively silylated with Tbdms-Cl and imidazole to yield the 3-beta-silylated compound (IV).The epoxidation of (IV) by means of tert-butyl hydroperoxide catalyzed by VO(acetonylacetonate)2 complex affords the corresponding epoxide (V),which is treated with PPh3 and CCl4 in dichloromethane to provide the 7-alpha-chloro derivative (VI).The desilylation of (VI) with HCl in THF/methanol gives the 3beta-hydroxy compound (VII),which is treated with Zn in AcOH/THF to yield 3beta,5beta-dihydroxy-15beta,16beta-methylene-6-androsten-17-one (VIII) (1).The cyclopropanation of (VIII) with diiodomethane and Zn in hot ethyleneglycol dimethylether gives 3beta,5beta-dihydroxy-6beta,7beta:15beta,16beta-bismethyleneandrostan-17-one (IX),which is condensed with propargyl alcohol (X) by means of K-OEt in THF,yielding 17alpha-(3-hydroxy-1-propynyl)-6beta,7beta:15beta,16beta-bismethyleneandrostan-3,5beta,17beta-triol (XI).The hydrogenation of (XI) with H2 over Pd/C in THF/methanol/pyridine affords the corresponding 17alpha-(3-hydroxypropyl) derivative (XII),which is finally oxidized,lactonized and dehydrated by means of CrO3 in hot pyridine/water.2.Alternatively,the 17alpha-(3-hydroxypropyl) derivative (XII) can be oxidized with RuCl3 and NaBrO3 in hot acetonitrile/water,giving the hydroxy carbolactone (XIII),which is finally dehydrated by means of Ts-OH in THF.3.Similar synthetic pathways have been described replacing the Tbdms protecting group with either dimethyl(3-methylbutyl)silyl or tribenzylsilyl groups.
合成路线:4.The fermentation of 3beta-hydroxy-15beta,16beta-methylene-17alpha-pregn-5-ene-21,17-carbolactone (I) with Botryodiplodia malorum gives the corresponding 3beta,7beta-dihydroxy derivative (II),which is regioselectively silylated with Tbdms-Cl and imidazole to yield the 3-beta-silylated compound (III).The epoxidation of (III) by means tert-butyl hydroperoxide catalyzed by VO2 acetonylacetonate complex affords the corresponding epoxide (IV),which is treated with PPh3 and CCl4 in dichloromethane to provide the 7-alpha-chloro derivative (V).The desilylation of (V) with HCl in THF/methanol gives the 3beta-hydroxy compound (VI),which is treated with Zn in AcOH/THF to yield 3beta,5beta-dihydroxy-15beta,16beta-methylene-17alpha-pregn-6-ene-21,17-carbolactone (VII).The cyclopropanation of (VII) with diiodomethane and Zn in hot ethyleneglycol dimethylether gives 3beta,5beta-dihydroxy-6beta,7beta:15beta,16beta-bismethylene-17-alpha-pregnan-21,17-carbolactone (VIII),which is finally oxidized and dehydrated by means of CrO3 in hot pyridine/water.
参考文献标题:Process for producing drospirenone (6beta,7beta;15beta,16beta-dimethylene-3-oxo-17alpha-preg-4-en-21,17-carbolactone,DRSP),as well as 7alpha-(3-hydroxy-1-propyl)-6beta,7beta;15beta,16beta-dimethylene-5beta-androstane-3beta,5,17beta-triol (ZK 92836) and
文献作者:Mohr,J.-T.; Nickisch,K.(Schering AG)
参考来源:DE 19633685; US 6121465; WO 9806738
合成路线: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.
合成路线:3) Reaction of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) with 1-bromo-3,3-dimethoxypropane (XIII) and lithium in THF gives the 17alpha-(3,3-dimethoxypropyl) derivative (XIV),which by treatment with 70% acetic acid provides the spiro compound (XV).Oxidation of compound (XV) with cyclohexanone in the presence of (i-PrO)3Al and then treatment with 2N H2SO4 affords 15beta,16beta-methylene-3-oxo-17alpha-pregn-4-ene-21,17-carbolactone (XVI).Treatment of (XVI) with chloranil in t-BuOH yields the pregnadiene carbolactone (XVII),which is finally reacted with trimethylsulfoxonium iodide (XVIII) and NaH in DMSO.
合成路线:4) The reaction of 6beta,7beta:15beta,16beta-dimethylene-4-androsten-3,17-dione (XIX) with 2-(1-ethoxyethoxy)-3-butenenitrile (XX) by means of BuLi and diisopropylamine (DIA) in THF gives the adduct (XXI),which is finally treated with LiBr and Li2CO3 in hot DMF .
合成路线:This compound has been obtained by different ways:1.The fermentation of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) or 3beta-acetoxy-15beta,16beta-methylene-5-androsten-17-one (II) with Botryodiplodia malorum gives the corresponding 3beta,7beta-dihydroxy derivative (III),which is regioselectively silylated with Tbdms-Cl and imidazole to yield the 3-beta-silylated compound (IV).The epoxidation of (IV) by means of tert-butyl hydroperoxide catalyzed by VO(acetonylacetonate)2 complex affords the corresponding epoxide (V),which is treated with PPh3 and CCl4 in dichloromethane to provide the 7-alpha-chloro derivative (VI).The desilylation of (VI) with HCl in THF/methanol gives the 3beta-hydroxy compound (VII),which is treated with Zn in AcOH/THF to yield 3beta,5beta-dihydroxy-15beta,16beta-methylene-6-androsten-17-one (VIII) (1).The cyclopropanation of (VIII) with diiodomethane and Zn in hot ethyleneglycol dimethylether gives 3beta,5beta-dihydroxy-6beta,7beta:15beta,16beta-bismethyleneandrostan-17-one (IX),which is condensed with propargyl alcohol (X) by means of K-OEt in THF,yielding 17alpha-(3-hydroxy-1-propynyl)-6beta,7beta:15beta,16beta-bismethyleneandrostan-3,5beta,17beta-triol (XI).The hydrogenation of (XI) with H2 over Pd/C in THF/methanol/pyridine affords the corresponding 17alpha-(3-hydroxypropyl) derivative (XII),which is finally oxidized,lactonized and dehydrated by means of CrO3 in hot pyridine/water.2.Alternatively,the 17alpha-(3-hydroxypropyl) derivative (XII) can be oxidized with RuCl3 and NaBrO3 in hot acetonitrile/water,giving the hydroxy carbolactone (XIII),which is finally dehydrated by means of Ts-OH in THF.3.Similar synthetic pathways have been described replacing the Tbdms protecting group with either dimethyl(3-methylbutyl)silyl or tribenzylsilyl groups.
合成路线:4.The fermentation of 3beta-hydroxy-15beta,16beta-methylene-17alpha-pregn-5-ene-21,17-carbolactone (I) with Botryodiplodia malorum gives the corresponding 3beta,7beta-dihydroxy derivative (II),which is regioselectively silylated with Tbdms-Cl and imidazole to yield the 3-beta-silylated compound (III).The epoxidation of (III) by means tert-butyl hydroperoxide catalyzed by VO2 acetonylacetonate complex affords the corresponding epoxide (IV),which is treated with PPh3 and CCl4 in dichloromethane to provide the 7-alpha-chloro derivative (V).The desilylation of (V) with HCl in THF/methanol gives the 3beta-hydroxy compound (VI),which is treated with Zn in AcOH/THF to yield 3beta,5beta-dihydroxy-15beta,16beta-methylene-17alpha-pregn-6-ene-21,17-carbolactone (VII).The cyclopropanation of (VII) with diiodomethane and Zn in hot ethyleneglycol dimethylether gives 3beta,5beta-dihydroxy-6beta,7beta:15beta,16beta-bismethylene-17-alpha-pregnan-21,17-carbolactone (VIII),which is finally oxidized and dehydrated by means of CrO3 in hot pyridine/water.
参考文献标题:Process for preparing 3beta,7beta-dihydroxy-DELTA5-steroids
文献作者:Nickisch,K.; Wiechert,R.; Laurent,H.; Petzoldt,K.; Bittler,D.(Schering AG)
参考来源:DE 3042136; EP 0051143; JP 1982122798; US 4416985; US 4614616
合成路线: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.
合成路线:3) Reaction of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) with 1-bromo-3,3-dimethoxypropane (XIII) and lithium in THF gives the 17alpha-(3,3-dimethoxypropyl) derivative (XIV),which by treatment with 70% acetic acid provides the spiro compound (XV).Oxidation of compound (XV) with cyclohexanone in the presence of (i-PrO)3Al and then treatment with 2N H2SO4 affords 15beta,16beta-methylene-3-oxo-17alpha-pregn-4-ene-21,17-carbolactone (XVI).Treatment of (XVI) with chloranil in t-BuOH yields the pregnadiene carbolactone (XVII),which is finally reacted with trimethylsulfoxonium iodide (XVIII) and NaH in DMSO.
合成路线:4) The reaction of 6beta,7beta:15beta,16beta-dimethylene-4-androsten-3,17-dione (XIX) with 2-(1-ethoxyethoxy)-3-butenenitrile (XX) by means of BuLi and diisopropylamine (DIA) in THF gives the adduct (XXI),which is finally treated with LiBr and Li2CO3 in hot DMF .
参考文献标题:Drospirenone
文献作者:Norman,P.; Casta馿r,R.M.; Casta馿r,J.
参考来源:Drugs Fut 2000,25(12),1247
合成路线: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.
合成路线:This compound has been obtained by different ways:1.The fermentation of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) or 3beta-acetoxy-15beta,16beta-methylene-5-androsten-17-one (II) with Botryodiplodia malorum gives the corresponding 3beta,7beta-dihydroxy derivative (III),which is regioselectively silylated with Tbdms-Cl and imidazole to yield the 3-beta-silylated compound (IV).The epoxidation of (IV) by means of tert-butyl hydroperoxide catalyzed by VO(acetonylacetonate)2 complex affords the corresponding epoxide (V),which is treated with PPh3 and CCl4 in dichloromethane to provide the 7-alpha-chloro derivative (VI).The desilylation of (VI) with HCl in THF/methanol gives the 3beta-hydroxy compound (VII),which is treated with Zn in AcOH/THF to yield 3beta,5beta-dihydroxy-15beta,16beta-methylene-6-androsten-17-one (VIII) (1).The cyclopropanation of (VIII) with diiodomethane and Zn in hot ethyleneglycol dimethylether gives 3beta,5beta-dihydroxy-6beta,7beta:15beta,16beta-bismethyleneandrostan-17-one (IX),which is condensed with propargyl alcohol (X) by means of K-OEt in THF,yielding 17alpha-(3-hydroxy-1-propynyl)-6beta,7beta:15beta,16beta-bismethyleneandrostan-3,5beta,17beta-triol (XI).The hydrogenation of (XI) with H2 over Pd/C in THF/methanol/pyridine affords the corresponding 17alpha-(3-hydroxypropyl) derivative (XII),which is finally oxidized,lactonized and dehydrated by means of CrO3 in hot pyridine/water.2.Alternatively,the 17alpha-(3-hydroxypropyl) derivative (XII) can be oxidized with RuCl3 and NaBrO3 in hot acetonitrile/water,giving the hydroxy carbolactone (XIII),which is finally dehydrated by means of Ts-OH in THF.3.Similar synthetic pathways have been described replacing the Tbdms protecting group with either dimethyl(3-methylbutyl)silyl or tribenzylsilyl groups.
合成路线:4.The fermentation of 3beta-hydroxy-15beta,16beta-methylene-17alpha-pregn-5-ene-21,17-carbolactone (I) with Botryodiplodia malorum gives the corresponding 3beta,7beta-dihydroxy derivative (II),which is regioselectively silylated with Tbdms-Cl and imidazole to yield the 3-beta-silylated compound (III).The epoxidation of (III) by means tert-butyl hydroperoxide catalyzed by VO2 acetonylacetonate complex affords the corresponding epoxide (IV),which is treated with PPh3 and CCl4 in dichloromethane to provide the 7-alpha-chloro derivative (V).The desilylation of (V) with HCl in THF/methanol gives the 3beta-hydroxy compound (VI),which is treated with Zn in AcOH/THF to yield 3beta,5beta-dihydroxy-15beta,16beta-methylene-17alpha-pregn-6-ene-21,17-carbolactone (VII).The cyclopropanation of (VII) with diiodomethane and Zn in hot ethyleneglycol dimethylether gives 3beta,5beta-dihydroxy-6beta,7beta:15beta,16beta-bismethylene-17-alpha-pregnan-21,17-carbolactone (VIII),which is finally oxidized and dehydrated by means of CrO3 in hot pyridine/water.
参考文献标题:
文献作者:
参考来源:Angew Chem 1982,94718-719
产品链接: CAS No. 67392-87-4››