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【结 构 式】 
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【药物名称】FK-143 【化学名称】4-[3-[3-[Bis(4-isobutylphenyl)methylamino]benzoyl]indol-1-yl]butyric acid 【CA登记号】163136-03-6, 139155-45-6 (monoHCl), 139155-29-6 (monoNa salt) 【 分 子 式 】C40H44N2O3 【 分 子 量 】600.80828 |
【开发单位】Fujisawa (Originator) 【药理作用】Benign Prostatic Hyperplasia Therapy, RENAL-UROLOGIC DRUGS, Steroid 5alpha-Reductase Inhibitors |
合成路线1
The Friedel-Crafts condensation of indole (I) with 3-nitrobenzoyl chloride (II) by means of AlCl3 in dichloromethane gives 3-(3-nitrobenzoyl)indole (III), which is allowed to react with ethyl 4-bromobutyrate (IV) by means of K2CO3 in DMF to yield 4-[3-(3-nitrobenzoyl)indol-1-yl]butyric acid ethyl ester (V). The hydrolysis of (V) with NaOH in dioxane/water affords the corresponding butyric acid (VI), which is hydrogenated with H2 over Pd/C in methanol/dioxane yielding 3-[3-(3-aminobenzoyl)indol-1-yl]butyric acid (VII). Finally, this compound is condensed with bis(4-isobutylphenyl)chloromethane (VIII) by means of ethyldiisopropylamine in dichloromethane.
| 【1】 Mealy, N.; Castaner, J.; FK-143. Drugs Fut 1996, 21, 5, 473. |
| 【2】 Golden, P.; Hashimoto, M.; Tanaka, H.; Sawada, Y.; Okada, S.; Sawada, K.; Kayakiri, N.; 4-(1-Benzoylindol-3-yl)butyric acids and FK143: Novel nonsteroidal inhibitors of steroid 5alpha-reductase (II). Chem Pharm Bull 1999, 47, 4, 481. |
| 【3】 Okada, S.; Sawada, K.; Kayakiri, N.; Saitoh, Y.; Tanaka, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); Indole derivs. EP 0458207; JP 1992244061; US 5212320; US 5312829 . |
| 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) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (II) | 15293 | 3-nitrobenzoyl chloride; m-nitrobenzoyl chloride | 121-90-4 | C7H4ClNO3 | 详情 | 详情 |
| (III) | 15294 | 1H-indol-3-yl(3-nitrophenyl)methanone | C15H10N2O3 | 详情 | 详情 | |
| (IV) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (V) | 15296 | ethyl 4-[3-(3-nitrobenzoyl)-1H-indol-1-yl]butanoate | C21H20N2O5 | 详情 | 详情 | |
| (VI) | 15297 | 4-[3-(3-nitrobenzoyl)-1H-indol-1-yl]butyric acid | C19H16N2O5 | 详情 | 详情 | |
| (VII) | 15298 | 4-[3-(3-aminobenzoyl)-1H-indol-1-yl]butyric acid | C19H18N2O3 | 详情 | 详情 | |
| (VIII) | 15299 | 1-[chloro(4-isobutylphenyl)methyl]-4-isobutylbenzene | C21H27Cl | 详情 | 详情 |