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【结 构 式】 
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【分子编号】33231 【品名】4-bromo-4'-fluoro-2-(hydroxymethyl)benzhydrol; [4-bromo-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanol 【CA登记号】 |
【 分 子 式 】C14H12BrFO2 【 分 子 量 】311.1504832 【元素组成】C 54.04% H 3.89% Br 25.68% F 6.11% O 10.28% |
合成路线1
该中间体在本合成路线中的序号：(IV)The reaction of 5-bromophthalide (I) with 4-fluorophenylmagnesium bromide (II) in ether gives 4-bromo-4'-fluoro-2-(hydroxymethyl)benzophenone (III), which is reduced with LiAlH4 or NaBH4 in ether to afford 4-bromo-4'-fluoro-2-(hydroxymethyl)benzhydrol (IV). The cyclization of (IV) with 60% H3PO4 or TsOH or H2SO4 at 100 C yields 5-bromo-1-(4-fluoropheny)phthalan (V), which by reaction with cuprous cyanide in refluxing DMF is converted into 1-(4-fluorophenyl)-5-phtalancarbonitrile (VI). Finally, this compound is condensed with 3-(dimethylamino)propyl chloride (A) by means of NaH in hot DMSO.
| 【1】 Bigler, A.J.; et al.; Quantitative structure-activity relationships in a series of selective 5-HT uptake inhibitors. Eur J Med Chem - Chim Ther 1977, 12, 3, 289-295. |
| 【2】 Bogeso, K.P.; Toft, A.S. (Kefalas A/S); Anti-depressive substituted 1-dimethylaminopropyl-1-phenyl phthalans. DE 2657013; FR 2338271; GB 1526331; JP 52105162; US 4136193 . |
| 【3】 Muddasani, P.R.; Nannapaneni, W.C. (Natco Pharma Ltd.); Process for the preparation of high purity citalopram and its pharmaceutically acceptable salts. WO 0416602 . |
| 【4】 Roberts, P.J.; Castaner, J.; Serradell, M.N.; Blancafort, P.; Citalopram. Drugs Fut 1979, 4, 6, 407. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 24581 | 3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine | 5407-04-5 | C5H12ClN | 详情 | 详情 |
| (I) | 33229 | 5-bromophthalide; 5-bromo-2-benzofuran-1(3H)-one | 64169-34-2 | C8H5BrO2 | 详情 | 详情 |
| (II) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (III) | 33230 | [4-Bromo-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanone; 4-Bromo-4'-fluoro-2-(hydroxymethyl)benzophenone | C14H10BrFO2 | 详情 | 详情 | |
| (IV) | 33231 | 4-bromo-4'-fluoro-2-(hydroxymethyl)benzhydrol; [4-bromo-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanol | C14H12BrFO2 | 详情 | 详情 | |
| (V) | 33232 | 5-bromo-1-(4-fluoropheny)phthalan; 5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran | C14H10BrFO | 详情 | 详情 | |
| (VI) | 33233 | 1-(4-fluorophenyl)-5-phtalancarbonitrile; 1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile | C15H10FNO | 详情 | 详情 |