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【结 构 式】 
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【分子编号】18040 【品名】(8S,10R,13S,14S)-3-methoxy-10,13-dimethyl-1,2,7,8,10,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one 【CA登记号】 |
【 分 子 式 】C20H26O2 【 分 子 量 】298.42524 【元素组成】C 80.5% H 8.78% O 10.72% |
合成路线1
该中间体在本合成路线中的序号：(XI)Reaction of 4,9(11)-androstadien-3,17-dione (III) with trimethyl orthoformate and TsOH in dioxane gives 3-methoxy-3,5,9(11)-androstatrien-17-one (XI), which is condensed with 1,2-dichloroethylene (XII) by means of MeLi in ethyl ether/THF to yield 17a-(chloroethynyl)-17b-hydroxy-4,9(11)-androstadien-3-one (XIII). Esterification of the OH group of (XIII) with fuming HNO3 and acetic anhydride affords the 17b-(nitrooxy) derivative (XIV), which is treated with formic acid and AgNO3 in N-methylpyrrolidone to provide 21-chloro-17a-(formyloxy)-4,9(11)-pregnadien-3,20-dione (XV). Hydrolysis of the formyloxy group of (XV) by means of KHCO3 in methanol/water gives 21-chloro-17a-hydroxy-4,9(11)-pregnadien-3,20-dione (XVI), which is finally acetylated by means of AcOK and KI in hot DMF.
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; Bayes, M.; Anecortave Acetate. Drugs Fut 2002, 27, 11, 1039. |
| 【2】 Annen, K.; Laurent, H.; Wiechert, R.; Hofmeister, H. (Schering AG); Process for the preparation of pregnane deriv.. DE 3434448; EP 0181442; US 4708823 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 56595 | (8S,10R,13S,14S)-10,13-dimethyl-7,8,10,12,13,14,15,16-octahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione | C19H24O2 | 详情 | 详情 | |
| (XI) | 18040 | (8S,10R,13S,14S)-3-methoxy-10,13-dimethyl-1,2,7,8,10,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | C20H26O2 | 详情 | 详情 | |
| (XII) | 28793 | (Z)-1,2-dichloroethene | 156-59-2 | C2H2Cl2 | 详情 | 详情 |
| (XIII) | 56603 | (8S,10R,13S,14S,17S)-17-(2-chloroethynyl)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H25ClO2 | 详情 | 详情 | |
| (XIV) | 56604 | (8S,10R,13S,14S,17S)-17-(2-chloroethynyl)-10,13-dimethyl-17-(nitrooxy)-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H24ClNO4 | 详情 | 详情 | |
| (XV) | 50605 | allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate | C18H34N2O5SSi | 详情 | 详情 | |
| (XVI) | 56606 | (8S,10R,13S,14S,17R)-17-(2-chloroacetyl)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H27ClO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Reaction of 3-methoxyandrosta-3,5,9(11)-trien-17-one (XI) with KCN and AcOH in methanol gives a 1:1 mixture of the epimeric cyanohydrins (XVII) and (XVIII) and the desired b-cyano epimer (XVIII) is obtained in a 95% yield by selective crystallization under equilibrating conditions. Protection of the 17-OH group of (XVIII) with TMS-Cl and imidazole yields the silyl ether (XIX), which is reduced with DIBAL and AcOH to afford the carbaldehyde (XX). Reaction of compound (XX) with dibromomethane and LDA provides the dibromo derivative (XXI), which by reaction with more LDA gives the lithium enolate (XXII). Hydrolysis of enolate (XXII) in acid medium yields the a-bromoketone (XXIII), which is acylated with AcOH and TEA in hot acetone to afford the silylated steroid (XXIV). Finally, compound (XXIV) is deprotected by means of HF and TEA in dichloromethane.
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; Bayes, M.; Anecortave Acetate. Drugs Fut 2002, 27, 11, 1039. |
| 【2】 Reid, J.G.; Debiak-Krook, T.; Corticoids from 17-oxosteroids. Tetrahedron Lett 1990, 31, 26, 3669. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 18040 | (8S,10R,13S,14S)-3-methoxy-10,13-dimethyl-1,2,7,8,10,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | C20H26O2 | 详情 | 详情 | |
| (XVII) | 56608 | (8S,10R,13S,14S,17S)-17-hydroxy-3-methoxy-10,13-dimethyl-2,7,8,10,12,13,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthrene-17-carbonitrile | C21H27NO2 | 详情 | 详情 | |
| (XVIII) | 56607 | (8S,10R,13S,14S,17R)-17-hydroxy-3-methoxy-10,13-dimethyl-2,7,8,10,12,13,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthrene-17-carbonitrile | C21H27NO2 | 详情 | 详情 | |
| (XIX) | 56609 | (8S,10R,13S,14S,17R)-3-methoxy-10,13-dimethyl-17-[(trimethylsilyl)oxy]-2,7,8,10,12,13,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthrene-17-carbonitrile | C24H35NO2Si | 详情 | 详情 | |
| (XX) | 56610 | (8S,10R,13S,14S,17R)-3-methoxy-10,13-dimethyl-17-[(trimethylsilyl)oxy]-2,7,8,10,12,13,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthrene-17-carbaldehyde | C24H36O3Si | 详情 | 详情 | |
| (XXI) | 56611 | 2,2-dibromo-1-{(8S,10R,13S,14S,17R)-3-methoxy-10,13-dimethyl-17-[(trimethylsilyl)oxy]-2,7,8,10,12,13,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-17-yl}-1-ethanol | C25H38Br2O3Si | 详情 | 详情 | |
| (XXII) | 56612 | lithium (Z)-2-bromo-1-{(8S,10R,13S,14S,17R)-3-methoxy-10,13-dimethyl-17-[(trimethylsilyl)oxy]-2,7,8,10,12,13,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-17-yl}-1-ethenolate | C25H36BrLiO3Si | 详情 | 详情 | |
| (XXIII) | 56613 | (8S,10R,13S,14S,17R)-17-(2-bromoacetyl)-10,13-dimethyl-17-[(trimethylsilyl)oxy]-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C24H35BrO3Si | 详情 | 详情 | |
| (XXIV) | 56614 | 2-{(8S,10R,13S,14S,17R)-10,13-dimethyl-3-oxo-17-[(trimethylsilyl)oxy]-2,3,6,7,8,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl}-2-oxoethyl acetate | C26H38O5Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)Condensation of 3-methoxyandrosta-3,5,9(11)-trien-17-one (XI) with 3-hydroxypropionitrile (XXV) by means of LDA in THF provides 17a-(1-cyano-2- hydroxyethyl)-17b-hydroxyandrosta-4,9(11)-dien-3-one (XXVI), which is selectively monoacetylated by means of Ac2O in pyridine to yield monoacetate (XXVII). Dehydration of (XXVII) by means of SOCl2 in pyridine gives 20-cyano-21-acetoxypregna-4,9(11),17(20)-trien-3-one (XXVIII), which is treated with ethylene glycol, trimethyl orthoformate and TsOH in dichloromethane to afford the ethylene ketal (XXIX). Finally, compound (XXIX) is oxidized with KMnO4 in acetone/ethylene glycol and treated with NaHSO3 and HCOOH.
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; Bayes, M.; Anecortave Acetate. Drugs Fut 2002, 27, 11, 1039. |
| 【2】 Walker, J.A. (Pharmacia Corp.); Corticosteroids from 17-keto steroids via 20-cyano-DELTA17(20)-pregnanes. US 4600538 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 | |
| (XI) | 18040 | (8S,10R,13S,14S)-3-methoxy-10,13-dimethyl-1,2,7,8,10,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | C20H26O2 | 详情 | 详情 | |
| (XXV) | 14029 | Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile | 109-78-4 | C3H5NO | 详情 | 详情 |
| (XXVI) | 56615 | 3-hydroxy-2-[(8S,10R,13S,14S,17R)-17-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]propanenitrile | C22H29NO3 | 详情 | 详情 | |
| (XXVII) | 56616 | 2-cyano-2-[(8S,10R,13S,14S,17R)-17-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethyl acetate | C24H31NO4 | 详情 | 详情 | |
| (XXVIII) | 56617 | 2-cyano-2-[(8S,10R,13S,14S)-10,13-dimethyl-3-oxo-1,2,3,6,7,8,10,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-ylidene]ethyl acetate | C24H29NO3 | 详情 | 详情 | |
| (XXIX) | 56618 | C26H33NO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)Condensation of 3-methoxyandrosta-3,5,9(11)-trien-17-one (XI) with (E)-1,2-dichloroethylene (XII) by means of BuLi in toluene gives 17a-[(E)-1,2-dichloro-vinyl]-17b-hydroxyandrosta-4,9(11)-dien-3-one (XXX), which is treated with phenylsulfenyl chloride and TEA in dichloromethane to yield 20,21-dichloro-21-(phenylsulfinyl)pregna-4,9(11),17(20)-trien-3-one (XXXI). Reac-tion of compound (XXXI) with MeONa in acetone/MeOH at 0 C affords 21-chloro-20-methoxy-21-(phenylsulfinyl)-pregna-4,9(11),17(20)-trien-3-one (XXXII), which by treatment with more MeONa at 35 C provides 21-chloro-17a-hydroxy-20-methoxypregna-4,9(11),20-trien-3-one (XXXIII). Hydrolysis of the enol ether of (XXXIII) with HCl in THF/acetone/MeOH gives the 3,20-dione derivative (XVI), which is finally treated with AcOK and KI in hot acetone/dichloromethane.
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; Bayes, M.; Anecortave Acetate. Drugs Fut 2002, 27, 11, 1039. |
| 【2】 Walker, J.A.; Hessler, E.J. (Pharmacia Corp.); Preparation of corticoids from 17-keto steroids. US 4357279 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 18040 | (8S,10R,13S,14S)-3-methoxy-10,13-dimethyl-1,2,7,8,10,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | C20H26O2 | 详情 | 详情 | |
| (XII) | 28793 | (Z)-1,2-dichloroethene | 156-59-2 | C2H2Cl2 | 详情 | 详情 |
| (XVI) | 56606 | (8S,10R,13S,14S,17R)-17-(2-chloroacetyl)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H27ClO3 | 详情 | 详情 | |
| (XXX) | 56619 | (8S,10R,13S,14S,17S)-17-[(E)-1,2-dichloroethenyl]-17-hydroxy-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H26Cl2O2 | 详情 | 详情 | |
| (XXXI) | 56620 | (8S,10R,13S,14S)-17-[(Z)-1,2-dichloro-2-(phenylsulfinyl)ethylidene]-10,13-dimethyl-7,8,10,12,13,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-3(2H,6H)-one | C27H30Cl2O2S | 详情 | 详情 | |
| (XXXII) | 56621 | (8S,10R,13S,14S)-17-[(Z)-2-chloro-1-methoxy-2-(phenylsulfinyl)ethylidene]-10,13-dimethyl-7,8,10,12,13,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-3(2H,6H)-one | C28H33ClO3S | 详情 | 详情 | |
| (XXXIII) | 56622 | (8S,10R,13S,14S,17R)-17-[(E)-2-chloro-1-methoxyethenyl]-17-hydroxy-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C22H29ClO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XI)Condensation of 3-methoxyandrosta-3,5,9(11)-trien-17-one (XI) with 2-chlorovinyl ethyl ether (XXXVI) by means of BuLi in THF gives 20-chloro-3-oxopregna-4,9(11),17(20)-trien-21-al (XXXVII), which is treated with Ac2O and AcOK in hot DMF to yield 21-(acetoxy)pregna-4,9(11),16-triene-3,20-dione (XXXVIII), Reaction of compound (XXXVIII) with RhCl(PPh3)3 and triethylsilane in hot dichloromethane affords 21-(acetoxy)-20-(triethyl-silyloxy)pregna-4,9(11),17(20)-trien-3-one (XXXIX), which is finally oxidized with peracetic acid in toluene, quenched with SO2 and treated with TEA.
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; Bayes, M.; Anecortave Acetate. Drugs Fut 2002, 27, 11, 1039. |
| 【2】 Van Rheenen, V.H.; Hessler, E.J. (Pharmacia Corp.); Synthesis of 16-unsaturated pregnanes from 17-keto steroids. US 4216159 . |
| 【3】 Walker, J.A. (Pharmacia Corp.); DELTA16-20-keto steroid conversion to 17alpha-hydroxy-20-keto steroids. US 4568492 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 18040 | (8S,10R,13S,14S)-3-methoxy-10,13-dimethyl-1,2,7,8,10,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | C20H26O2 | 详情 | 详情 | |
| (XXXVI) | 56625 | (E)-1-chloro-2-ethoxyethene; (E)-2-chloroethenyl ethyl ether | C4H7ClO | 详情 | 详情 | |
| (XXXVII) | 56626 | 2-chloro-2-[(8S,10R,13S,14S)-10,13-dimethyl-3-oxo-1,2,3,6,7,8,10,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-ylidene]acetaldehyde | C21H25ClO2 | 详情 | 详情 | |
| (XXXVIII) | 56627 | 2-[(8S,10R,13S,14S)-10,13-dimethyl-3-oxo-2,3,6,7,8,10,12,13,14,15-decahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | 23460-76-6 | C23H28O4 | 详情 | 详情 |
| (XXXIX) | 56628 | 2-[(8S,10R,13S,14S)-10,13-dimethyl-3-oxo-1,2,3,6,7,8,10,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-ylidene]-2-[(triethylsilyl)oxy]ethyl acetate | C29H44O4Si | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XIV)Starting from enol ether (XIV), its reaction with the sulfonium ylide from trimethylsulfonium methylsulfate and KOH in DMSO-THF at 80 C afforded epoxide (XV). This was converted to the lactone (XVI) by treatment with diethyl malonate and sodium ethoxide in refluxing ethanol, and then decarboxylated to (XVII) on heating with NaCl in moist DMF. Hydrolysis of enol ether with AcOH in boiling ethanol-water provided dienone (XVIII), which was oxidized to trienone (XIX) by means of a sequence consisting of halogenation with N-bromosuccinimide and then dehydrohalogenation with DABCO and LiBr in DMF. Using the analogous reactions as in Scheme 1, (XIX) was converted to enamine (XX), then hydrolyzed to diketone (XXI), treated with NaOMe to give dienone (XXII), and finally converted to the target epoxide.
| 【1】 Ng, J.S.; Wang, P.T.; Baez, J.A.; Liu, C.; Anderson, D.K.; Lawson, J.P.; Erb, D.; Wieczorek, J.; Mucciariello, G.; Vanzanella, F.; Kunda, S.A.; Letendre, L.J.; Pozzo, M.J.; Sing, Y.-L.L. (Pharmacia Corp.); Process for preparation of 7 alpha-carboxyl 9,11-epoxy steroids and intermediates useful therein and a general process for the epoxidation of olifinic double bonds. WO 9721720 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 18040 | (8S,10R,13S,14S)-3-methoxy-10,13-dimethyl-1,2,7,8,10,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | C20H26O2 | 详情 | 详情 | |
| (XV) | 18041 | 3-Methoxyspiro[androsta-3,5,9(11)-triene-17(S),2'-oxirane] | C21H28O2 | 详情 | 详情 | |
| (XVI) | 18042 | 21-(Ethoxycarbonyl)-3-methoxypregan-3,5,9(11)-triene-21,17-carbolactone | C26H34O5 | 详情 | 详情 | |
| (XVII) | 18043 | 3-Methoxypregna-3,5,9(11)-triene-21,17-carbolactone | C23H30O3 | 详情 | 详情 | |
| (XVIII) | 18044 | 3-Oxopregna-4,9(11)-diene-21,17-carbolactone | C22H28O3 | 详情 | 详情 | |
| (XIX) | 18045 | 3-Oxopregan-4,6,9(11)-triene-21,17-carbolactone | C22H26O3 | 详情 | 详情 | |
| (XX) | 18046 | 4'-Amino-5-beta-cyano-7-alpha,4-metheno-3-oxo-17-alpha-pregn-9(11)-ene-21,17-carbolactone | C24H28N2O3 | 详情 | 详情 | |
| (XXI) | 18047 | 5-beta-Cyano-4,7-alpha-methano-3,4'-dioxo-17-alpha-pregn-9(11)-ene-21,17-carbolactone | C24H27NO4 | 详情 | 详情 | |
| (XXII) | 18034 | 7-Alpha-(methoxycarbonyl)-3-oxopregna-4,9(11)-diene-21,17-carbolactone | C24H30O5 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XIV)Alternatively, lactone (XVIII) obtained from enol ether (XIV) as in the Scheme 3, was epoxidized to give (XXIII), which was dehydrogenated using either DDQ or chloranil to afford dienone (XXIV). Conversion to enamine (XXV), then hydrolysis to diketone (XXVI), and ring opening with NaOMe furnished eplerenone.
| 【1】 Ng, J.S.; Wang, P.T.; Baez, J.A.; Liu, C.; Anderson, D.K.; Lawson, J.P.; Erb, D.; Wieczorek, J.; Mucciariello, G.; Vanzanella, F.; Kunda, S.A.; Letendre, L.J.; Pozzo, M.J.; Sing, Y.-L.L. (Pharmacia Corp.); Process for preparation of 7 alpha-carboxyl 9,11-epoxy steroids and intermediates useful therein and a general process for the epoxidation of olifinic double bonds. WO 9721720 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 18040 | (8S,10R,13S,14S)-3-methoxy-10,13-dimethyl-1,2,7,8,10,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | C20H26O2 | 详情 | 详情 | |
| (XV) | 18041 | 3-Methoxyspiro[androsta-3,5,9(11)-triene-17(S),2'-oxirane] | C21H28O2 | 详情 | 详情 | |
| (XVI) | 18042 | 21-(Ethoxycarbonyl)-3-methoxypregan-3,5,9(11)-triene-21,17-carbolactone | C26H34O5 | 详情 | 详情 | |
| (XVII) | 18043 | 3-Methoxypregna-3,5,9(11)-triene-21,17-carbolactone | C23H30O3 | 详情 | 详情 | |
| (XVIII) | 18044 | 3-Oxopregna-4,9(11)-diene-21,17-carbolactone | C22H28O3 | 详情 | 详情 | |
| (XXIII) | 18048 | 9-alpha,11-alpha-Epoxy-3-oxopregn-4-ene-21,17-carbolactone | C22H28O4 | 详情 | 详情 | |
| (XXIV) | 18049 | 9-alpha,11-alpha-Epoxy-3-oxopregna-4,6-diene-21,17-carbolactone | C22H26O4 | 详情 | 详情 | |
| (XXV) | 18050 | 4'-Amino-5-beta-cyano-9-alpha,11-alpha-epoxy-7-alpha,4-metheno-3-oxo-17-alpha-pregnane-21,17-carbolactone | C24H28N2O4 | 详情 | 详情 | |
| (XXVI) | 18051 | 5-beta-Cyano-9-alpha,11-alpha-epoxy-4,7-alpha-methano-3,4'-dioxo-17-alpha-pregnane-21,17-carbolactone | C24H27NO5 | 详情 | 详情 |