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【结 构 式】 
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【分子编号】34210 【品名】(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 【CA登记号】50-28-2 |
【 分 子 式 】C18H24O2 【 分 子 量 】272.38736 【元素组成】C 79.37% H 8.88% O 11.75% |
合成路线1
该中间体在本合成路线中的序号：(I)The benzoylation of 1,3,5(10)-estratrien-3,17beta-diol (I) with benzoyl chloride (II) by means of NaOH in THF-water gives 3-benzoyloxy-1,3,5(10)-estratrien-17beta-ol (III), which is acylated with bromoacetyl bromide (IV) by means of pyridine in THF-CCl4 yielding 3-benzoyloxy-17beta-bromoacetoxy 1,3,5(10)-estratriene (V). Finally, this compound is condensed with silver 4-[4-[bis(2-chloroethyl)amino]phenyl]butyrate (VI) in DMSO.
| 【1】 Asano, K.; Tamura, H.; Tanaka, H.; Enomoto, S.; Novel estradiol compound, its preparation and anti-tumor agent containing the same. BE 0878186; JP 55027121 . |
| 【2】 Castaner, J.; Serradell, M.N.; KM-2210. Drugs Fut 1984, 9, 5, 334. |
| 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) | 10643 | (1S,2S,3R,4S,7S,8S,10R,13S)-10-(acetoxy)-1,7-bis(benzyloxy)-13-[[tert-butyl(dimethyl)silyl]oxy]-8,12,15,15-tetramethyl-5,9-dioxo-4-[(phenylsulfanyl)methyl]tricyclo[9.3.1.0(3,8)]pentadec-11-en-2-yl benzoate | C55H66O9SSi | 详情 | 详情 | |
| (III) | 34211 | (8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl benzoate | C25H28O3 | 详情 | 详情 | |
| (IV) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (V) | 34212 | (8R,9S,13S,14S,17S)-17-[(2-bromoacetyl)oxy]-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl benzoate | C27H29BrO4 | 详情 | 详情 | |
| (VI) | 34213 | silver(1+) 4-[4-[bis(2-chloroethyl)amino]phenyl]butanoate | C14H18AgCl2NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Estradiol 3-N-bis(2-chloroethyl)carbamate (IV) was prepared by treatment of estradiol (I) with either the carbamoyl chloride (II) or the carbamoyl bromide (III) in the presence of various bases such as triethylamine and DMAP or DBU. Phosphorylation of (IV) with phosphorus oxychloride and pyridine, followed by aqueous hydrolysis, produced the 17-O-phosphate ester (V). This was converted to the corresponding disodium salt by treatment with sodium methoxide.
| 【1】 Stamvik, A.R.; Kristensson, S.K. (Leo Pharma AB); A selective acylation process. EP 0138153 . |
| 【2】 Ohwaki, K.; Niino, H.; Method for selective acylation of estradiol. EP 0614909 . |
| 【3】 Ohwaki, K.; Niino, H.; norose, S.; Method for purification of estramustin phosphate or salt thereof. EP 0612760 . |
| 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) | 56313 | N,N-Bis(2-chloroethyl)carbamoyl chloride; Bis(2-chloroethyl)carbamoyl chloride | 2998-56-3 | C5H8Cl3NO | 详情 | 详情 |
| (III) | 56314 | 1-[(bromocarbonyl)(2-chloroethyl)amino]-2-chloroethane | C5H8BrCl2NO | 详情 | 详情 | |
| (IV) | 56315 | (8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl bis(2-chloroethyl)carbamate | C23H31Cl2NO3 | 详情 | 详情 | |
| (V) | 56316 | (8R,9S,13S,14S,17S)-13-methyl-17-(phosphonooxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl bis(2-chloroethyl)carbamate | C23H32Cl2NO6P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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4
该中间体在本合成路线中的序号：(I)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. |