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【结 构 式】 
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【药物名称】PNU-109291 【化学名称】(-)-1(S)-[2-[4-(4-Methoxyphenyl)piperazin-1-yl]ethyl]-Nmethyl- 3,4-dihydro-1H-2-benzopyran-6-carboxamide 【CA登记号】 【 分 子 式 】C24H31N3O3 【 分 子 量 】409.53297 |
【开发单位】Pharmacia & Upjohn 【药理作用】ANALGESIC AND ANESTHETIC DRUGS，ANTIMIGRAINE DRUGS |
合成路线1
The cyclization of 2-(3-bromophenyl)ethyl alcohol (I) with ethyl 3,3-diethoxypropionate by means of TiCl4 in dichlromethane gives racemic 2-(6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)acetic acid ethyl ester (III), which is regioselectively hydrolyzed by means of Amano P-30 lipase in apH 7 buffer yielding 2-(6-bromo-3,4-dihydro-1H-2-benzopyran-1(S)-yl)acetic acid (IV). The condensation of (IV) with 1-(4-methoxyphenyl)piperazine (V) by means of diethyl cyanophosphate in dichloromethane affords the acylated piperazine (VI), which is reduced with the complex BH3.THF in THF to 6-bromo-1(S)-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-3,4-dihydro-1H-2-benzopyran (VII). The reaction of (VII) with trimethylsilyl isocyante (VIII) by means of BuLiDMF gives the crboxamide (IX), which is treated with di-tert-butyl dicarbonate and dimethylaminopyridine (DMAP) in dichloromethane to yield the N,N-bis(tert-butoxycarbonyl) derivative (X). Finally, this compound is treated with an excess of methylamine.
| 【1】 Ennis, M.D.; Tenbrink, R.E. (Pharmacia & Upjohn AB); 1,6-Disubstd. isochromans for treatment of migraine headaches. EP 0836599; JP 1999509532; WO 9702259 . |
| 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) | 19969 | 2-(3-bromophenyl)-1-ethanol; 3-Bromophenethyl alcohol | 28229-69-8 | C8H9BrO | 详情 | 详情 |
| (II) | 17901 | Ethyl 3,3-diethoxypropanoate | 10601-80-6 | C9H18O4 | 详情 | 详情 |
| (III) | 19971 | ethyl 2-(6-bromo-3,4-dihydro-1H-isochromen-1-yl)acetate | C13H15BrO3 | 详情 | 详情 | |
| (IV) | 19972 | ethyl 2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]acetate | C13H15BrO3 | 详情 | 详情 | |
| (V) | 16312 | 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether | 38212-30-5 | C11H16N2O | 详情 | 详情 |
| (VI) | 19974 | 2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]-1-[4-(4-methoxyphenyl)-1-piperazinyl]-1-ethanone | C22H25BrN2O3 | 详情 | 详情 | |
| (VII) | 19975 | 1-[2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]ethyl]-4-(4-methoxyphenyl)piperazine; 4-(4-[2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]ethyl]-1-piperazinyl)phenyl methyl ether | C22H27BrN2O2 | 详情 | 详情 | |
| (VIII) | 19976 | isocyanato(trimethyl)silane; trimethylsilyl isocyanate | C4H9NOSi | 详情 | 详情 | |
| (IX) | 19977 | (1S)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-3,4-dihydro-1H-isochromene-6-carboxamide | C23H29N3O3 | 详情 | 详情 | |
| (X) | 19978 | 1-[2-((1S)-6-[[bis(tert-butoxycarbonyl)amino]carbonyl]-3,4-dihydro-1H-isochromen-1-yl)ethyl]-4-(4-methoxyphenyl)piperazine | C33H45N3O7 | 详情 | 详情 |