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【结 构 式】 
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【分子编号】44332 【品名】4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile 【CA登记号】 |
【 分 子 式 】C20H23FN2O2 【 分 子 量 】342.4133032 【元素组成】C 70.15% H 6.77% F 5.55% N 8.18% O 9.35% |
合成路线1
该中间体在本合成路线中的序号：(VII)The Grignard condensation of 5-cyanophthalide (I) with 4-fluorophenylmagnesium bromide (II) in THF gives 1-(4-fluorophenyl)-1-hydroxy-1,3-dihydroisobenzofuran-5-carbonitrile bromomagnesium salt (III), which slowly rearranges to the benzophenone (IV). A new Grignard condensation of (IV) with 3-(dimethylamino)propylmagnesium chloride (V) in THF affords the expected bis(magnesium) salt (VI), which is hydrolyzed with acetic acid to provide the diol (VII) as a racemic mixture. Selective esterification of the primary alcohol of (VII) with (+)-3,3,3-trifluoro-2-methoxy-2-phenylacetyl chloride (VIII) gives the monoester (IX) as a mixture of diastereomers. This mixture is separated by HPLC and the desired diastereomer (X) is treated with potassium tert-butoxide in toluene.
| 【1】 Sorbera, L.A.; Martin, L.; Revel, L.; Castaner, J.; Escitalopram oxalate. Drugs Fut 2001, 26, 2, 115. |
| 【2】 Boegesoe, K.P.; Perregaard, J. (H. Lundbeck A/S); New enantiomers and their isolation. AU 8936295; EP 0347066; JP 1990036177; JP 1999292867; US 4943590 . |
| 【3】 Bogeso, K.P. (H. Lundbeck A/S); Novel intermediate and method for its preparation. US 4650884 . |
| 【4】 Petersen, H.; Dancer, R.; Nielsen, O.; Rock, M.H.; Humble, R.E.; Christensen, T.V. (H. Lundbeck A/S); Process for the preparation of racemic citalopram and/or S- or R-citalopram by separation of a mixture of R- and S-citalopram. WO 0300672 . |
| 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) | 37601 | 1-oxo-1,3-dihydro-2-benzofuran-5-carbonitrile | 82104-74-3 | C9H5NO2 | 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) | 44329 | C15H9BrFMgNO2 | 详情 | 详情 | ||
| (IV) | 44330 | C15H9BrFMgNO2 | 详情 | 详情 | ||
| (V) | 12587 | Chloro[3-(dimethylamino)propyl]magnesium | C5H12ClMgN | 详情 | 详情 | |
| (VI) | 44331 | C20H21BrClFMg2N2O2 | 详情 | 详情 | ||
| (VII) | 44332 | 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile | C20H23FN2O2 | 详情 | 详情 | |
| (VIII) | 44333 | 3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride | C10H8ClF3O2 | 详情 | 详情 | |
| (IX) | 44334 | 5-cyano-2-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]benzyl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate | C30H30F4N2O4 | 详情 | 详情 | |
| (X) | 44335 | 5-cyano-2-[(1S)-4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]benzyl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate | C30H30F4N2O4 | 详情 | 详情 | |
| (XI) | 44336 | 4-[(1S)-4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile | C20H23FN2O2 | 详情 | 详情 |