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【结 构 式】 
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【药物名称】ID-4708 【化学名称】1-(2-Amino-4-fluorophenyl)-4-[4-hydroxy-4-[3-(trifluoromethyl)phenyl]piperidin-1-yl]butan-1-one 【CA登记号】42048-72-6, 50528-46-6 (hydrochloride) 【 分 子 式 】C22H24F4N2O2 【 分 子 量 】424.44238 |
【开发单位】 【药理作用】 |
合成路线1
The condensation of 6-fluoro-2-methylindole (I) with beta-chloropropionitrile (II) by means of ethylmagnesium iodide (that forms the magnesium salt of (I)) in refluxing ether gives 3-(6-fluoro-2-methyl-3-indolyl)propionitrite (III), which is hydrolyzed with KOH in refluxing water yielding 3-(6-fluoro-2-methyl-3-indolyl)propionic acid (IV) (1). The condensation of (IV) with 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (V) by means of ethyl chloroformate and triethylamine in refluxing THF affords 1-[3-(6-fluoro-2-methyl-3-indolyl)propionyl]-4-hydroxy-4-(3-trifluromethylphenyl)piperidine (VI), which is reduced with LiAlH4 in refluxing THF giving 1-[3-(6-fluoro-2-methyl-3-indolyl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (VII). The ozonolysis of (VII) in HOAc affords 1-[3-(2-acetamido-4-fluorobenzoyl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (VIII), which is finally hydrolyzed with concentrated HCl in refluxing EtOH
| 【1】 (Sumitomo Chemical Co., Ltd.); FR 2196153 . |
| 【2】 Yamamoto, H.; et al. (Sumitomo Chemical Co., Ltd.); DE 2065311; JP 754670; JP 754671 . |
| 【3】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Owen, R.T.; ID - 4708. Drugs Fut 1979, 4, 7, 492. |
| 【4】 Honma, T.; et al.; The XIAP antisense compound AEG35156/GEM640 demonstrates significant antitumor activity in multiple human cancer xenograft models. Arzneim-Forsch 1974, 24, 9, 1248. |
| 【5】 Yamamoto, H.; et al. (Sumitomo Chemical Co., Ltd.); 3-Hetero-substd.-N-benzyl-indoles. US 3907812 . |
| 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) | 61098 | 6-fluoro-2-methyl-1H-indole | C9H8FN | 详情 | 详情 | |
| (II) | 30744 | 3-chloropropanenitrile | 542-76-7 | C3H4ClN | 详情 | 详情 |
| (III) | 61099 | 3-(6-fluoro-2-methyl-1H-indol-3-yl)propanenitrile | C12H11FN2 | 详情 | 详情 | |
| (IV) | 61100 | 3-(6-fluoro-2-methyl-1H-indol-3-yl)propanoic acid | C12H12FNO2 | 详情 | 详情 | |
| (V) | 61101 | 4-[3-(trifluoromethyl)phenyl]-4-piperidinol | C12H14F3NO | 详情 | 详情 | |
| (VI) | 61102 | 3-(6-fluoro-2-methyl-1H-indol-3-yl)-1-{4-hydroxy-4-[3-(trifluoromethyl)phenyl]-1-piperidinyl}-1-propanone | C24H24F4N2O2 | 详情 | 详情 | |
| (VII) | 61103 | 1-[3-(6-fluoro-2-methyl-1H-indol-3-yl)propyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidinol | C24H26F4N2O | 详情 | 详情 | |
| (VIII) | 61104 | N-[5-fluoro-2-(4-{4-hydroxy-4-[3-(trifluoromethyl)phenyl]-1-piperidinyl}butanoyl)phenyl]acetamide | C24H26F4N2O3 | 详情 | 详情 |
合成路线2
The reaction of 4-fluoro-2-nitrobenzoic acid (IX) with refluxing SOCl2 gives the corresponding acyl chloride (X), which is then condensed with alpha-acetyl-gamma-butyrolactone (XI) by means of Mg(OEt)2 in toluene yielding alpha-acetyl-alpha-(4-fluoro-2-nitrobenzoyl)-gamma-butyrolactone (XII). The hydrolysis of (XII) with HCl affords alpha-(4-fluoro-2-nitrobenzoyl)-gamma-butyrolactone (XIII), which by treatment with HBr (d, 1.48) at 85 C is converted into gamma-bromo-4-fluoro-2-nitrobutyrophenone (XIV). The ketalization of (XIV) with ethyleneglycol and ethylenesulfite by means of p-toluenesulfonic acid in refluxing toluene yields the corresponding ketal (XV), which is condensed with the piperidine (V) by means of K2CO3 in hot methyl isobutylketone giving 4-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidino]-1-(4-fluoro-2-nitrophenyl)-1,1-ethylenedioxy-n-butane (XVI). The hydrolysis of (XVI) HCl in refluxing isopropanol affords gamma-[hydroxy-4-(3-trifluoromethylphenyl)piperidino]-4-fluoro-2-nitrobutyrophenone (XVII), which is finally reduced with H2 over Pd/C in MeOH The direct condensation of butyrophenone (XIV) with piperidine (V) by means of K2CO3 as before gives the already obtained butyrophenone (XVII).
| 【1】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Owen, R.T.; ID - 4708. Drugs Fut 1979, 4, 7, 492. |
| 【2】 Sasajima, K.; et al. (Sumitomo Chemical Co., Ltd.); DE 2632414 . |
| 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) | 61101 | 4-[3-(trifluoromethyl)phenyl]-4-piperidinol | C12H14F3NO | 详情 | 详情 | |
| (IX) | 61105 | 4-fluoro-2-nitrobenzoic acid | C7H4FNO4 | 详情 | 详情 | |
| (X) | 61106 | 4-fluoro-2-nitrobenzoyl chloride | C7H3ClFNO3 | 详情 | 详情 | |
| (XI) | 24709 | 3-acetyldihydro-2(3H)-furanone | 517-23-7 | C6H8O3 | 详情 | 详情 |
| (XII) | 61107 | 3-acetyl-3-(4-fluoro-2-nitrobenzoyl)dihydro-2(3H)-furanone | C13H10FNO6 | 详情 | 详情 | |
| (XIII) | 61108 | 3-(4-fluoro-2-nitrobenzoyl)dihydro-2(3H)-furanone | C11H8FNO5 | 详情 | 详情 | |
| (XIV) | 61109 | 4-bromo-1-(4-fluoro-2-nitrophenyl)-1-butanone | C10H9BrFNO3 | 详情 | 详情 | |
| (XV) | 61110 | 2-(3-bromopropyl)-2-(4-fluoro-2-nitrophenyl)-1,3-dioxolane | C12H13BrFNO4 | 详情 | 详情 | |
| (XVI) | 61389 | 1-{3-[2-(4-fluoro-2-nitrophenyl)-1,3-dioxolan-2-yl]propyl}-4-[3-(trifluoromethyl)phenyl]-4-piperidinol | C24H26F4N2O5 | 详情 | 详情 | |
| (XVII) | 61390 | 1-(4-fluoro-2-nitrophenyl)-4-{4-hydroxy-4-[3-(trifluoromethyl)phenyl]-1-piperidinyl}-1-butanone | C22H22F4N2O4 | 详情 | 详情 |