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【结 构 式】 
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【分子编号】19528 【品名】6-fluoro-2-chromanecarboxylic acid 【CA登记号】 |
【 分 子 式 】C10H9FO3 【 分 子 量 】196.1780632 【元素组成】C 61.22% H 4.62% F 9.68% O 24.47% |
合成路线1
该中间体在本合成路线中的序号：(II)The reduction of 6-fluoro-4-oxobenzopyran-2-carboxylic acid (I) with H2 over Pd/C in acetic acid gives 6-fluoro-3,4-dihydro-2H-benzopyran-2-carboxylic acid (II), which is reduced again with bis(2-methylpropyl)aluminum hydride and 1,1'-carbonylbis(1H-imidazole) in THF yielding 6-fluoro-3,4-dihydro-2H-benzopyran-2-carboxaldehyde (III). The reaction of (III) with trimethylsulfoxonium iodide and NaH in DMSO affords 2-oxiranyl-3,4-dihydro-2H-benzopyran (IV), which is condensed with benzylamine (V) in refluxing ethanol to give the benzyl derivative of nebivolol (VI). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol.
| 【1】 Van Lommen, G.R.E.; De Bruyn, M.F.L.; Schroven, M.F.J. (Janssen Pharmaceutica NV); Derivatives of 2,2'-iminobisethanol.. AU 8436326; EP 145067; JP 85132977; US 4654362 . |
| 【2】 Prous, J.; Castaner, J.; NEBIVOLOL < Prop INN; USAN >. Drugs Fut 1989, 14, 10, 957. |
| 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) | 19527 | 4-oxo-4H-chromene-2-carboxylic acid | C10H5FO4 | 详情 | 详情 | |
| (II) | 19528 | 6-fluoro-2-chromanecarboxylic acid | C10H9FO3 | 详情 | 详情 | |
| (III) | 19529 | 6-fluoro-2-chromanecarbaldehyde | C10H9FO2 | 详情 | 详情 | |
| (IV) | 19530 | 6-fluoro-2-(2-oxiranyl)chromane | C11H11FO2 | 详情 | 详情 | |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 19532 | 2-[benzyl[2-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)-2-hydroxyethyl]amino]-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)-1-ethanol | C29H31F2NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)
| 【1】 Sheth R, Attanti SV, Patel HM, et al.2006.Nebivolol and its pharmaceutically acceptable salts, process for preparation and pharmaceutical compositions of nebivolol. WO 2006025070. |
| 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) | 60391 | 1-(5-fluoro-2-hydroxyphenyl)-1-ethanone | 394-32-1 | C8H7FO2 | 详情 | 详情 |
| (II) | 67329 | 6-fluoro-4-oxo-4H-chromene-2-carboxylic acid, sodium salt | C10H5FO4.Na | 详情 | 详情 | |
| (III) | 19528 | 6-fluoro-2-chromanecarboxylic acid | C10H9FO3 | 详情 | 详情 | |
| (IV) | 67330 | (6-fluorochroman-2-yl)(piperidin-1-yl)methanone | C15H18FNO2 | 详情 | 详情 | |
| (V) | 19529 | 6-fluoro-2-chromanecarbaldehyde | C10H9FO2 | 详情 | 详情 | |
| (VI) | 40863 | (2R)-6-fluoro-2-[(2R)oxiranyl]-3,4-dihydro-2H-chromene | C11H11FO2 | 详情 | 详情 | |
| (VII) | 67317 | 2-(benzylamino)-1-(6-fluorochroman-2-yl)ethanol | C18H20FNO2 | 详情 | 详情 | |
| (VIII) | 67318 | (S)-1-((R)-6-fluorochroman-2-yl)-2-(((S)-2-((S)-6-fluorochroman-2-yl)-2-hydroxyethyl)(phenyl)amino)ethanol | C28H29F2NO4 | 详情 | 详情 | |
| (XI) | 67300 | (R)-6-fluoro-2-((R)-oxiran-2-yl)chroman | C11H11FO2 | 详情 | 详情 |