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【结 构 式】 
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【分子编号】50978 【品名】(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 【CA登记号】 |
【 分 子 式 】C25H28O2 【 分 子 量 】360.49612 【元素组成】C 83.29% H 7.83% O 8.88% |
合成路线1
该中间体在本合成路线中的序号：(VI)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2
该中间体在本合成路线中的序号：(I)Claisen condensation of 3-O-benzylestrone (I) with ethyl formate in the presence of NaH afforded the 16-hydroxymethylene derivative (II), which was further converted to enol ether (III) by alkylation with ethyl iodide. Stereoselective ketone reduction of (III) with LiAlH4 gave the 17-beta alcohol (IV), which was esterified with Ac2O in pyridine to provide acetate (V). Acid hydrolysis of the enol ether of (V) produced the 16-alpha aldehyde (VI), and subsequent Jones oxidation furnished the carboxylic acid (VII). After basic hydrolysis of the acetate ester of (VII) to yield (VIII), its O-benzyl protecting group was removed by hydrogenolysis over Pd/C, yielding diol (IX). Finally, Fischer esterification with 2-fluoroethanol in the presence of p-toluenesulfonic acid gave rise to the title fluoroethyl ester.
| 【1】 Labaree, D.C.; et al.; Estradiol-16alpha-carboxylic acid esters as locally active estrogens. J Med Chem 2001, 44, 11, 1802. |
| 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) | 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 | |
| (II) | 50979 | (8R,9S,13S,14S)-3-(benzyloxy)-16-[(Z)-hydroxymethylidene]-13-methyl-7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]phenanthren-17-one | C26H28O3 | 详情 | 详情 | |
| (III) | 50980 | (8R,9S,13S,14S)-3-(benzyloxy)-16-[(Z)-ethoxymethylidene]-13-methyl-7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]phenanthren-17-one | C28H32O3 | 详情 | 详情 | |
| (IV) | 50981 | (8R,9S,13S,14S,17R)-3-(benzyloxy)-16-[(Z)-ethoxymethylidene]-13-methyl-6,7,8,9,11,12,13,14,15,17-decahydro-16H-cyclopenta[a]phenanthren-17-ol | C28H34O3 | 详情 | 详情 | |
| (V) | 50982 | (8R,9S,13S,14S,17R)-3-(benzyloxy)-16-[(Z)-ethoxymethylidene]-13-methyl-6,7,8,9,11,12,13,14,15,17-decahydro-16H-cyclopenta[a]phenanthren-17-yl acetate | C30H36O4 | 详情 | 详情 | |
| (VI) | 50983 | (8R,9S,13S,14S,16R,17S)-3-(benzyloxy)-16-formyl-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate | C28H32O4 | 详情 | 详情 | |
| (VII) | 50984 | (8R,9S,13S,14S,16R,17S)-17-(acetoxy)-3-(benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-16-carboxylic acid | C28H32O5 | 详情 | 详情 | |
| (VIII) | 50985 | (8R,9S,13S,14S,16R,17S)-3-(benzyloxy)-17-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-16-carboxylic acid | C26H30O4 | 详情 | 详情 | |
| (IX) | 50986 | (8R,9S,13S,14S,16R,17S)-3,17-dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-16-carboxylic acid | C19H24O4 | 详情 | 详情 |