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【结 构 式】 
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【药物名称】Acolbifene hydrochloride, EM-01538, SCH-57068.HCl, EM-652.HCl 【化学名称】3-(4-Hydroxyphenyl)-4-methyl-2(S)-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-7-ol hydrochloride 【CA登记号】252555-01-4, 182167-02-8 (free base) 【 分 子 式 】C29H32ClNO4 【 分 子 量 】494.03569 |
【开发单位】Endorecherche (Originator), Schering-Plough (Not Determined) 【药理作用】Breast Cancer Therapy, ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , Oncolytic Drugs, Treatment of Postmenopausal Syndrome , Antiestrogens |
合成路线1
The reaction of 1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)-ethanone (I) with DHP and Ts-OH in ethyl acetate gives the bis-tetrahydropyranyl ether (II), which is condensed with the benzaldehyde (III) by means of piperidine in 2-butanol to yield a mixture of the propenone (IV) and the benzopyranone (V). This mixture, without isolation, is treated with DBU to convert (IV) into (V). The methylation of (V) with MeLi in tert-butyl methyl ether affords the benzopyran-4-ol (VI), which is treated with (S)-(+)-camphorsulfonic acid (VII) to provide the dehydrated benzopyran camphorsulfonate (VIII) as a diastereomeric mixture that is separated by crystallization. The desired isomer (IX) is treated with TEA to give the title compound (X) as free base that is finally treated with HCl in EtOH/water to yield the desired hydrochloride.
| 【1】 Gauthier, S.; et al.; Synthesis and structure-activity relationships of analogs of EM-652, a pure selective estrogen receptor modulator. Part 1: Study of nitrogen substitution. 223rd ACS Natl Meet (April 7 2002, Orlando) 2002, Abst MEDI 224. |
| 【2】 Lu, Y.; Draper, R.W.; Iyer, R.V.; Vater, E.J. (Schering Corp.); Enantioselective synthesis. US 6262270 . |
| 【3】 Lu, Y.; Draper, R.W.; Iyer, R.V.; Vater, E.J. (Schering Corp.); Enantioselective synthesis. WO 0009493 . |
| 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) | 51229 | 1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)-1-ethanone | C14H12O4 | 详情 | 详情 | |
| (II) | 51230 | 1-[2-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-1-ethanone | C24H28O6 | 详情 | 详情 | |
| (III) | 35795 | 4-[2-(1-piperidinyl)ethoxy]benzaldehyde | 26815-04-3 | C14H19NO2 | 详情 | 详情 |
| (IV) | 53981 | (E)-1-[2-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-3-{4-[2-(1-piperidinyl)ethoxy]phenyl}-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2-propen-1-one | n/a | C38H45NO7 | 详情 | 详情 |
| (V) | 53982 | (2R,3S)-5-hydroxy-2-{4-[2-(1-piperidinyl)ethoxy]phenyl}-7-(tetrahydro-2H-pyran-2-yloxy)-3-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2,3-dihydro-4H-chromen-4-one | n/a | C38H45NO8 | 详情 | 详情 |
| (VI) | 53983 | (2R,3S)-4-methyl-2-{4-[2-(1-piperidinyl)ethoxy]phenyl}-7-(tetrahydro-2H-pyran-2-yloxy)-3-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-3,4-dihydro-2H-chromene-4,5-diol | n/a | C39H49NO8 | 详情 | 详情 |
| (VII) | 53984 | (+/-)-Camphor-10-sulphonic acid; (?-10-Camphorsulfonic acid; DL-Camphor-10-sulfonic acid; DL-10-Camphorsulfonic acid; DL-Camphor-10-sulfonic acid; DL-Oxo-10-Bornanesulfonic acid | 5872-08-2 | C10H16O4S | 详情 | 详情 |
| (VIII) | 53985 | 1-(2-{4-[5,7-dihydroxy-3-(4-hydroxyphenyl)-4-methyl-2H-chromen-2-yl]phenoxy}ethyl)piperidinium (7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonate | n/a | C39H47NO9S | 详情 | 详情 |
| (IX) | 53986 | 1-(2-{4-[(2S)-5,7-dihydroxy-3-(4-hydroxyphenyl)-4-methyl-2H-chromen-2-yl]phenoxy}ethyl)piperidinium (7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonate | n/a | C39H47NO9S | 详情 | 详情 |
| (X) | 53987 | (2S)-3-(4-hydroxyphenyl)-4-methyl-2-{4-[2-(1-piperidinyl)ethoxy]phenyl}-2H-chromene-5,7-diol | n/a | C29H31NO5 | 详情 | 详情 |