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【结 构 式】 
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【药物名称】 【化学名称】4-[3-[3-[3-[4-(2-Ethoxyphenyl)piperazin-1-yl]propoxy]-4-(4-methylbenzyloxy)benzoyl]indol-1-yl]butyric acid potassium salt 【CA登记号】173364-91-5 【 分 子 式 】C42H46KN3O6 【 分 子 量 】727.95342 |
【开发单位】Zeria (Originator) 【药理作用】Benign Prostatic Hyperplasia Therapy, RENAL-UROLOGIC DRUGS, alpha1-Adrenoceptor Antagonists, Steroid 5alpha-Reductase Inhibitors |
合成路线1
Title compound was prepared by two synthetic ways. Friedel-Crafts acylation of N-(phenylsulfonyl)indole (II) with acid chloride (I) with concomitant O-debenzylation in the presence of AlCl3 yielded ketone (III). Then, hydroxyl group alkylation of (III) with alpha-bromo-p-xylene (IV) provided p-methylbenzyl ether (V). Subsequent displacement of the chloro group in (IV) by 1-(2-ethoxyphenyl)piperazine (VI) furnished (VII). After hydrolysis of sulfonyl group of (VII) with KOH, the resulting deprotected indole (VIII) was alkylated with ethyl 4-bromobutyrate to give (IX). Finally, hydrolysis of the ethyl ester of (IX) by means of ethanolic KOH provided the title carboxylic acid potassium salt.
| 【1】 Sato, H.; et al.; Dual-acting agents with alpha1-adrenoceptor antagonistic and steroid 5 alpha-reductase inhibitory activities. Synthesis and evaluation of arylpiperazine derivatives. Bioorg Med Chem Lett 1999, 9, 11, 1553. |
| 【2】 Yoshida, K.; Kurimoto, T.; Takei, M.; Sato, H. (Zeria Pharmaceutical Co., Ltd.); Indole deriv. and medicine containing the same. EP 0753511; US 5760040; WO 9526955 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 | |
| (I) | 26120 | 4-(benzyloxy)-3-(3-chloropropoxy)benzoyl chloride | C17H16Cl2O3 | 详情 | 详情 | |
| (II) | 26121 | 1-(phenylsulfonyl)-1H-indole | 40899-71-6 | C14H11NO2S | 详情 | 详情 |
| (III) | 26122 | [3-(3-chloropropoxy)-4-hydroxyphenyl][1-(phenylsulfonyl)-1H-indol-3-yl]methanone | C24H20ClNO5S | 详情 | 详情 | |
| (IV) | 24623 | 1-(bromomethyl)-4-methylbenzene | 104-81-4 | C8H9Br | 详情 | 详情 |
| (V) | 26123 | [3-(3-chloropropoxy)-4-[(4-methylbenzyl)oxy]phenyl][1-(phenylsulfonyl)-1H-indol-3-yl]methanone | C32H28ClNO5S | 详情 | 详情 | |
| (VI) | 23055 | ethyl 2-(1-piperazinyl)phenyl ether; 1-(2-ethoxyphenyl)piperazine | C12H18N2O | 详情 | 详情 | |
| (VII) | 26124 | [3-[3-[4-(2-ethoxyphenyl)-1-piperazinyl]propoxy]-4-[(4-methylbenzyl)oxy]phenyl][1-(phenylsulfonyl)-1H-indol-3-yl]methanone | C44H45N3O6S | 详情 | 详情 | |
| (VIII) | 26125 | [3-[3-[4-(2-ethoxyphenyl)-1-piperazinyl]propoxy]-4-[(4-methylbenzyl)oxy]phenyl](1H-indol-3-yl)methanone | C38H41N3O4 | 详情 | 详情 | |
| (IX) | 26126 | ethyl 4-(3-[3-[3-[4-(2-ethoxyphenyl)-1-piperazinyl]propoxy]-4-[(4-methylbenzyl)oxy]benzoyl]-1H-indol-1-yl)butanoate | C44H51N3O6 | 详情 | 详情 |
合成路线2
In a related procedure, dihydroxybenzoyl indole (X) was selectively alkylated at 4-hydroxyl group with alpha-bromo-p-xylene (IV) to provide ether (XI). Further alkylation of (XI) with 1-bromo-3-chloropropane gave (XII). Then, halogen displacement in (XII) by piperazine (VI) furnished the precursor ethyl ester (IX), which was finally hydrolyzed to the target carboxylic acid as above.
| 【1】 Sato, H.; et al.; Dual-acting agents with alpha1-adrenoceptor antagonistic and steroid 5 alpha-reductase inhibitory activities. Synthesis and evaluation of arylpiperazine derivatives. Bioorg Med Chem Lett 1999, 9, 11, 1553. |
| 【2】 Yoshida, K.; Kurimoto, T.; Takei, M.; Sato, H. (Zeria Pharmaceutical Co., Ltd.); Indole deriv. and medicine containing the same. EP 0753511; US 5760040; WO 9526955 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 | |
| (IV) | 24623 | 1-(bromomethyl)-4-methylbenzene | 104-81-4 | C8H9Br | 详情 | 详情 |
| (VI) | 23055 | ethyl 2-(1-piperazinyl)phenyl ether; 1-(2-ethoxyphenyl)piperazine | C12H18N2O | 详情 | 详情 | |
| (IX) | 26126 | ethyl 4-(3-[3-[3-[4-(2-ethoxyphenyl)-1-piperazinyl]propoxy]-4-[(4-methylbenzyl)oxy]benzoyl]-1H-indol-1-yl)butanoate | C44H51N3O6 | 详情 | 详情 | |
| (X) | 26127 | ethyl 4-[3-(3,4-dihydroxybenzoyl)-1H-indol-1-yl]butanoate | C21H21NO5 | 详情 | 详情 | |
| (XI) | 26128 | ethyl 4-(3-[3-hydroxy-4-[(4-methylbenzyl)oxy]benzoyl]-1H-indol-1-yl)butanoate | C29H29NO5 | 详情 | 详情 | |
| (XII) | 26129 | ethyl 4-(3-[3-(3-chloropropoxy)-4-[(4-methylbenzyl)oxy]benzoyl]-1H-indol-1-yl)butanoate | C32H34ClNO5 | 详情 | 详情 |