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【结 构 式】 
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【药物名称】2-Methoxyestradiol, NSC-659853, 2-ME, 2ME2, Panzem 【化学名称】2-Methoxyestra-1,3,5(10)-triene-3,17beta-diol 【CA登记号】362-07-2 【 分 子 式 】C19H26O3 【 分 子 量 】302.41727 |
【开发单位】Tetrionics (Supplier), EntreMed (Orphan Drug), Children's Hospital of Boston (Originator), Allergan (Licensee), EntreMed (Licensee), Aventis Pharma (Codevelopment) 【药理作用】Bone Diseases, Treatment of, Breast Cancer Therapy, METABOLIC DRUGS, Multiple Myeloma Therapy, OCULAR MEDICATIONS, Oncolytic Drugs, Ophthalmic Drugs, Prevention of Osteoporosis, Prostate Cancer Therapy, Solid Tumors Therapy, Treatment of Age-Related Macular Degeneration, Treatment of Osteoporosis, Angiogenesis Inhibitors, Apoptosis Inducers, Estrogens, Microtubule-Stabilizing Agents |
合成路线1
Estradiol (I) was brominated employing either bromine in acetic acid, 2,4,4,6-tetrabromocyclohexa-2,5-dienone, or N-bromosuccinimide to afford a mixture of 4-bromo (II) and 2-bromo (III) derivatives, which were separated by fractional crystallization. The target methoxy compound was then obtained by nucleophilic displacement of the bromide group from the 2-bromo isomer (III) by means of sodium methoxide in the presence of cuprous iodide and, optionally, a crown ether.
| 【1】 Narashima Rao, P.; Burdett, Jr.E.; A Novel, Two-Step Synthesis of 2-Methoxyestradiol. Synthesis 1977, 10, 3, 168-169. |
| 【2】 Chen, S.-H.; et al.; A new synthetic route to 2-and 4-methoxyestradiols by nucleophilic substitution. Steroids 1986, 47, 1, 63. |
| 【3】 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 |
|---|---|---|---|---|---|---|
| (I) | 34210 | (8R,9S,13S,14S,17S)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol | 50-28-2 | C18H24O2 | 详情 | 详情 |
| (II) | 59407 | (8R,9S,13S,14S,17S)-4-bromo-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol | C18H23BrO2 | 详情 | 详情 | |
| (III) | 59408 | (8R,9S,13S,14S,17S)-2-bromo-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol | C18H23BrO2 | 详情 | 详情 |
合成路线2
In a related procedure, the known 2-iodoestradiol (IV), regioselectively obtained by iodination of (I), was displaced with either sodium or barium methoxide to give the title compound. In this case, cupric iodide was preferred as the reaction catalyst.
| 【1】 Ogura, Y.; Numazawa, M.; Efficient synthesis of 2-methoxy- and 4-methoxy-estrogens. J Chem Soc Chem Commun 1983, 9, 533. |
| 【2】 Numazawa, M.; et al.; Synthesis of 2-methoxy- and 4-methoxy-estrogens with halogen-methoxy exchange reactions. J Chem Res Synop 1985, 11, 348. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 59409 | (8R,9S,13S,14S,17S)-2-iodo-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol | C18H23IO2 | 详情 | 详情 |
合成路线3
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4
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5
A similar synthetic strategy was used starting from the methoxymethyl-protected compound (XV). Baeyer-Villiger oxidation of the aldehyde function in the presence of phosphate buffer produced the formate ester (XVI), which was further hydrolyzed to phenol (XVII) under basic conditions. Methylation of phenol (XVII) with iodomethane employing a phase-transfer catalyst gave the methyl ether (XVIII). The methoxymethyl protecting groups were finally removed by acidic treatment.
| 【1】 Cushman, M.; Wang, Z.; An optimized synthesis of 2-methoxyestradiol, a naturally occurring human metabolite with anticancer activity. Synth Commun 1998, 28, 23, 4431. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 59418 | (8R,9S,13S,14S,17S)-3,17-bis(methoxymethoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-2-carbaldehyde | C23H32O5 | 详情 | 详情 | |
| (XVI) | 59419 | (8R,9S,13S,14S,17S)-3,17-bis(methoxymethoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-2-yl formate | C23H32O6 | 详情 | 详情 | |
| (XVII) | 59420 | (8R,9S,13S,14S,17S)-3,17-bis(methoxymethoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-2-ol | C22H32O5 | 详情 | 详情 | |
| (XVIII) | 59421 | (8R,9S,13S,14S,17S)-3,17-bis(methoxymethoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-2-yl methyl ether; (8R,9S,13S,14S,17S)-2-methoxy-3,17-bis(methoxymethoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene | C23H34O5 | 详情 | 详情 |
合成路线6
Friedel-Crafts acylation of 3-deoxyestradiol acetate (XIX) employing acetyl chloride and AlCl3 afforded the 2-acetylated compound (XX) as the major isomer. This was subjected to Baeyer-Villiger oxidation with peracetic acid to give diacetate (XXI), which was further hydrolyzed to diol (XXII) under basic conditions. Alkylation of the phenolic hydroxyl using dimethyl sulfate in the presence of KOH furnished the methyl ether (XXIII). After esterifying the aliphatic alcohol with acetic anhydride in pyridine, the resultant compound (XXIV) was subjected to a new cycle of Friedel-Crafts acetylation and Baeyer-Villiger oxidation yielding the 3,17-diacetate (XXVI). Finally, basic hydrolysis of the acetate esters provided the target compound.
| 【1】 Nambara, T.; et al.; Studies on steroid conjugates. III. New syntheses of 2-methoxyestrogens. Chem Pharm Bull 1970, 18, 3, 474. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 59422 | (8R,9S,13S,14S,17S)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate | C20H26O2 | 详情 | 详情 | |
| (XX) | 59423 | (8R,9S,13S,14S,17S)-2-acetyl-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate | C22H28O3 | 详情 | 详情 | |
| (XXI) | 59424 | (8R,9S,13S,14S,17S)-17-(acetyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-2-yl acetate | C22H28O4 | 详情 | 详情 | |
| (XXII) | 59425 | (8R,9S,13S,14S,17S)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-2,17-diol | C18H24O2 | 详情 | 详情 | |
| (XXIII) | 59426 | (8R,9S,13S,14S,17S)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-ol | C19H26O2 | 详情 | 详情 | |
| (XXIV) | 59427 | (8R,9S,13S,14S,17S)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate | C21H28O3 | 详情 | 详情 | |
| (XXV) | 59428 | (8R,9S,13S,14S,17S)-3-acetyl-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate | C23H30O4 | 详情 | 详情 | |
| (XXVI) | 59429 | (8R,9S,13S,14S,17S)-17-(acetyloxy)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl acetate | C23H30O5 | 详情 | 详情 |
合成路线7
In a related method starting from estradiol 3-methyl ether 17-acetate (XXVII), Friedel-Crafts acetylation in the presence of AlCl3 gave ketone (XXVIII). The methyl ether group was then cleaved employing HBr in HOAc to afford phenol (XXIX). Protection of phenol (XXIX) as the benzyl ether, followed by reacetylation of the 17-hydroxyl group furnished (XXX), which was further subjected to Baeyer-Villiger oxidation to provide diacetate (XXXI). Hydrolysis of (XXXI) under basic conditions gave diol (XXXII). Methylation of (XXXII) by means of diazomethane provided the 2-methoxy derivative (XXXIII). The O-benzyl protecting group was finally removed by catalytic hydrogenolisis.
| 【1】 Nambara, T.; et al.; Studies on steroid conjugates. III. New syntheses of 2-methoxyestrogens. Chem Pharm Bull 1970, 18, 3, 474. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXVII) | 59430 | (8R,9S,13S,14S,17S)-3-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate | C21H28O3 | 详情 | 详情 | |
| (XXVIII) | 59431 | (8R,9S,13S,14S,17S)-2-acetyl-3-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate | C23H30O4 | 详情 | 详情 | |
| (XXIX) | 59432 | (8R,9S,13S,14S,17S)-2-acetyl-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate | C22H28O4 | 详情 | 详情 | |
| (XXX) | 59433 | (8R,9S,13S,14S,17S)-2-acetyl-3-(benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate | C29H34O4 | 详情 | 详情 | |
| (XXXI) | 59434 | (8R,9S,13S,14S,17S)-17-(acetyloxy)-3-(benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-2-yl acetate | C29H34O5 | 详情 | 详情 | |
| (XXXII) | 59435 | (8R,9S,13S,14S,17S)-3-(benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-2,17-diol | C25H30O3 | 详情 | 详情 | |
| (XXXIII) | 59436 | (8R,9S,13S,14S,17S)-3-(benzyloxy)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-ol | C26H32O3 | 详情 | 详情 |
合成路线8
In a further procedure, estradiol (I) was complexed with in situ prepared [Cp*Ir(acetone)3][BF4]2 to afford, after deprotonation with Et3N, the dienone-iridium complex (XXXIVa-b) as a mixture of alpha and beta isomers. The major alpha isomer was isolated by fractional crystallization and subsequently treated with sodium methoxide in MeOH at -40 C to furnish selectively the 2-methoxy adduct (XXXV). Subsequent oxidative decomplexation with iodine in acetonitrile provided the target 2-methoxyestradiol.
| 【1】 Le Bras, J.; et al.; Activation and regioselective ortho-functionalization of the A-ring of beta-estradiol promoted by "Cp*Ir": An efficient organometallic procedure for the synthesis of 2-methoxyestradiol. Organometallics 1997, 16, 8, 1765. |