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【结 构 式】 
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【分子编号】20468 【品名】(8R,9S,13S,14S)-3-hydroxy-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one 【CA登记号】53-16-7 |
【 分 子 式 】C18H22O2 【 分 子 量 】270.37148 【元素组成】C 79.96% H 8.2% O 11.84% |
合成路线1
该中间体在本合成路线中的序号：(I)By esterification of estrone (I) with chlosulfonamide (II) and NaH in DMF.
| 【1】 Potter, B.V.L.; Howarth, N.M.; Purohit, A.,; Reed, M.J.; Steroid sulphatase inhibitors: a new endocrine therapy. Drugs Fut 1994, 19, 7, 673. |
| 【2】 Reed, M.J.; Potter, B.V.L.; Purohit, A.,; Howarth, N.M.; Cooper, G.; Duncan, L.J.; Phosphonates and thiophosphonates as sulfate surrogates: Synthesis of estrone 3-methylthiophosphonate a potent inhibitor of estrone sulfatase. Bioorg Med Chem Lett 1993, 3, 2, 313-318. |
合成路线2
该中间体在本合成路线中的序号：(I)Oleoyl-estrone can be obtained by direct condensation of commercially available estrone (I) and oleoyl chloride (II) in anhydrous pyridine at 40 C.
| 【1】 Sanchis, D.; Balada, F.; Picó, C.; Grasa, M.M.; Virgili, J.; Farrerons, C.; Palou, A.; Fernández-López, J.A.; Remesar, X.; Alemany, M.; Rats receiving the slimming agent oleoyl-estrone in liposomes (Merlin-2) decrease food intake but maintain thermogenesis. Arch Physiol Biochem 1997, 105, 7, 663. |
| 【2】 del Fresno, M.; Cullell-Young, M.; Oleoyl-Estrone. Drugs Fut 2002, 27, 7, 648. |
| 【3】 Alemany, M. (Laboratorios Salvat SA); Fatty-acid monoesters of estrogens for the treatment of obesity and/or overweight. EP 0771817; US 5798348 . |
合成路线3
该中间体在本合成路线中的序号：(III)Grignard reagent (II) was prepared from 3-bromobenzyl halide (I) in Et2O at 0 C, and subsequently added to estrone (III) to provide the target carbinol.
| 【1】 Poirier, D.; Boivin, R.P.; 17alpha-Alkyl- or 17alpha-substituted benzyl-17beta-estradiols: A new family of estrone-sulfatase inhibitors. Bioorg Med Chem Lett 1998, 8, 14, 1891. |
合成路线4
该中间体在本合成路线中的序号：(III)Grignard reagent (II), prepared from 4-tert-butylbenzyl bromide (I) and magnesium in Et2O, was condensed with estrone (III) to provide the 17-(tert-butylbenzyl)estradiol (IV). Subsequent reaction of (IV) with sulfamoyl chloride in the presence of 2,6-di-tert-butyl-4-methylpyridine (DBMP) yielded the title sulfamate ester.
| 【1】 Labrie, F.; Boivin, R.P.; Luu-The, V.; Ciobanu, L.C.; Poirier, D.; Potent inhibition of steroid sulfatase activity by 3-O-sulfamate 17alpha-Benzyl(or 4'-tert-butylbenzyl)estra-1,3,5(10)-trienes: Combination of two substituents at positions C3 and c17alpha of estradiol. J Med Chem 1999, 42, 12, 2280. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40598 | amidosulfonoyl chloride | 7778-42-9 | H2ClNO2S | 详情 | 详情 | |
| (I) | 20588 | 1-(bromomethyl)-4-(tert-butyl)benzene | 18880-00-7 | C11H15Br | 详情 | 详情 |
| (II) | 34441 | bromo[4-(tert-butyl)benzyl]magnesium | C11H15BrMg | 详情 | 详情 | |
| (III) | 20468 | (8R,9S,13S,14S)-3-hydroxy-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | 53-16-7 | C18H22O2 | 详情 | 详情 |
| (IV) | 34442 | (8R,9S,13S,14S,17R)-17-[4-(tert-butyl)benzyl]-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol | C29H38O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)In an alternative method, the hydroxyl group of estrone (V) was protected as the benzyl ether (VI), which was subsequently subjected to electrophilic nitration to yield selectively the 2-nitro derivative (VII). After reduction of (VII) to the corresponding amine (VIII), replacement of the amino for a methoxy group was performed by diazotization, followed by treatment with sodium methoxide, using Sandmeyer conditions. Finally hydrogenolysis of the O-benzyl protecting group, with simultaneous ketone reduction led to the desired 2-methoxy estradiol.
| 【1】 Shah, J.H.; Agoston, G.E.; Treston, A.M. (EntreMed, Inc.); Methods of obtaining 2-methoxyestradiol of high purity. WO 0114405 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 20468 | (8R,9S,13S,14S)-3-hydroxy-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | 53-16-7 | C18H22O2 | 详情 | 详情 |
| (VI) | 50978 | (8R,9S,13S,14S)-3-(benzyloxy)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | C25H28O2 | 详情 | 详情 | |
| (VII) | 59410 | (8R,9S,13S,14S)-3-(benzyloxy)-13-methyl-2-nitro-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | C25H27NO4 | 详情 | 详情 | |
| (VIII) | 59411 | (8R,9S,13S,14S)-2-amino-3-(benzyloxy)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | C25H29NO2 | 详情 | 详情 | |
| (IX) | 59412 | (8R,9S,13S,14S)-3-(benzyloxy)-2-methoxy-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | C26H30O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Formylation of estradiol (I) with hexamethylenetetraamine in refluxing trifluoroacetic acid gave the desired 2-formyl estradiol (XI) along with minor amounts of the 4-formyl isomer (X). Diol (XI) was then protected as the bis-benzyl ether (XII) by alkylation with benzyl bromide and NaH under phase-transfer conditions. Baeyer-Villiger oxidation of aldehyde (XII) with m-chloroperbenzoic acid provided phenol (XIII), wich was further alkylated with iodomethane to afford the methyl ether (XIV). The benzyl protecting groups were finally removed by catalytic hydrogenolysis.
| 【2】 Cushman, M.; et al.; Synthesis, antitubulin and antimitotic activity, and cytotoxicity of analogs of 2-methoxyestradiol, an endogenous mammalian metabolite of estradiol that inhibits tubulin polymerization by binding to the colchicine binding site. J Med Chem 1995, 38, 12, 2041. |
| 【1】 Cushman, H.-M.; He, H.-M.; A versatile synthesis of 2-methoxyestradiol, an endogenous metabolite of estradiol which inhibits tubulin polymerization by binding the colchicine binding site. Bioorg Med Chem Lett 2002, 4, 14, 1725. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 20468 | (8R,9S,13S,14S)-3-hydroxy-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | 53-16-7 | C18H22O2 | 详情 | 详情 |
| (X) | 59413 | (8R,9S,13S,14S,17S)-3,17-dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-4-carbaldehyde | C19H24O3 | 详情 | 详情 | |
| (XI) | 59414 | (8R,9S,13S,14S,17S)-3,17-dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-2-carbaldehyde | C19H24O3 | 详情 | 详情 | |
| (XII) | 59415 | (8R,9S,13S,14S,17S)-3,17-bis(benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-2-carbaldehyde | C33H36O3 | 详情 | 详情 | |
| (XIII) | 59416 | (8R,9S,13S,14S,17S)-3,17-bis(benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-2-ol | C32H36O3 | 详情 | 详情 | |
| (XIV) | 59417 | benzyl (8R,9S,13S,14S,17S)-17-(benzyloxy)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl ether; (8R,9S,13S,14S,17S)-3,17-bis(benzyloxy)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene | C33H38O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The title compound is obtained by Friedel-Crafts alkylation of estrone (I) with 1 adamantanol (II) in the presence of boron trifluoride etherate.
| 【1】 Covey, D.F. (Washington University); Modified, hydroxy-substd. aromatic structures having cytoprotective activity. WO 0236605 . |